Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals

ABSTRACT

The present invention relates to substituted 2-(chroman-6-yloxy)-thiazoles of the formula I, 
                         
in which Ar, R2, R3 and R4 are as defined in the claims. The compounds of the formula I are inhibitors of the sodium-calcium exchanger (NCX), especially of the sodium-calcium exchanger of subtype 1 (NCX1), and are suitable for the treatment of diverse disorders in which intracellular calcium homeostasis is disturbed, such as arrhythmias, heart failure and stroke. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use as pharmaceuticals, and pharmaceutical compositions comprising them.

The present invention relates to substituted2-(chroman-6-yloxy)thiazoles of the formula I,

in which Ar, R2, R3 and R4 are as defined below. The compounds of theformula I are inhibitors of the sodium-calcium exchanger (NCX),especially of the sodium-calcium exchanger of subtype 1 (NCX1), and aresuitable for the treatment of diverse disorders in which intracellularcalcium homeostasis is disturbed, such as arrhythmias, heart failure andstroke. The invention furthermore relates to processes for thepreparation of the compounds of the formula I, their use aspharmaceuticals, and pharmaceutical compositions comprising them.

Over the last decade major pharmacologic advances have been realized inthe management of heart failure (HF), or congestive heart failure (CHF).Beta-blockers and inhibitors of the renin-angiotensin-aldosterone systemhave been found to have a favorable effect in CHF with regard tomortality and improvement of symptoms (K. Dickstein et al., Eur. J.Heart Fail. 10 (2008): 933-989). Nevertheless, morbidity and mortalityhave remained unacceptably high. The number of patients with CHF, and inparticular more severe forms of CHF, is even growing, in partparadoxically because of the success of these treatment approaches.Thus, there is still a need for agents that can help improve CHF outcomeand enhance quality of life. Blockers of the sodium-calcium exchanger(NCX), a transport protein which is involved in the regulation ofcellular calcium and sodium levels, have the potential to improve theprognosis of CHF and quality of life.

The function of the NCX is to extrude calcium in cardiomyocytes andother cell types such as neurons. In CHF, the NCX was shown to beupregulated, thus unloading the cell from calcium and further decreasingmyocardial contractility (M. Flesch et al., Circulation 94 (1996):992-1002; G. Hasenfuss et al., Circulation 99 (1999): 641-648). Pumpfailure in CHF is not only due to irreversible structural changes andloss of myocardium, but also due to adverse functional changes includinga disturbance of the intracellular calcium homeostasis. The latter canbe treated by inhibition of the NCX. Three subtypes of the NCX have beendescribed. In the heart, predominantly subtype 1 is expressed.

Through the NCX, calcium is exchanged for sodium, and extracellularsodium is the driving force for the exchanger. The stoichiometry of theexchanger is that three sodium ions enter the cell for the extrusion ofone calcium ion. This stoichiometry causes a positive inward currentwhich is depolarizing in nature. The depolarizing current, if of asufficient size, gives rise to a certain type of arrhythmias which iscalled delayed after depolarizations (DADs) (D. M. Bers et al., Ann.N.Y. Acad. Sci. 1080 (2006): 165-177; K. R. Sipido et al., PflugersArch. 430 (1995): 871-878; A. O. Verkerk et al., Circulation 104 (2001):2728-2733). This type of arrhythmias is also called triggered activity.The premature beats arising from the NCX-induced depolarizing currentscan cause more complex and irreversible arrhythmias such as episodes oftachycardia, ventricular flutter or ventricular fibrillation.

Patients with pump failure, or heart failure, typically suffer fromarrhythmias and arrhythmic death. About 50% of the mortality in CHF isdue to arrhythmic death. NCX blockade is therefore a means of improvingpump failure and associated symptoms as well as of reducing arrhythmicdeath. Current positive inotropic drugs are associated withproarrhythmic effects that either increase mortality, such as in thecase of phosphodiesterase inhibitors, or annihilate the positive effectsachieved by an improvement of pump failure by the positive inotropiceffect (J. T. Parissis et al., Curr. Opin. Crit. Care 16 (2010):432-441). On the other hand, a number of clinically usefulantiarrhythmic drugs have a negative inotropic effect on the heartworsening the symptoms of heart failure. NCX blockers aretherapeutically unique in that they can address the two major problemsof CHF, pump failure and arrhythmias.

NCX blockade is particularly interesting for advanced stages of CHF,like NYHA Classes III and IV according to the New York Heart AssociationFunctional Classification of heart failure, in which the therapeuticoptions, i.e. beta-blockers, inhibitors of the reninangiotensin-aldosterone system, diuretics and vasodilators, already arefully exploited. Elderly patients progressing to end-stage HF present anew emerging population. In this late stage a vasodilator effect is nomore desirable in a considerable part of the patients because bloodpressure is already lowered as a consequence of pump failure.Phosphodiesterase inhibitors as positive inotropic drugs not only sufferfrom the drawback of being proarrhythmic, but also from a vasodilatoreffect.

Atrial fibrillation (AF) is the most frequent arrhythmia. AF affectsabout 6.8 million patients in the US and the European Union, and itsprevalence is strongly rising because of the aging of the population andof the successful treatment of myocardial infarction, coronary arterydisease and congestive heart failure. AF causes about 25% of allstrokes, and increases mortality. Also in AF, upregulation of the NCXhas been demonstrated (U. Schotten et al., Cardiovasc. Res. 53 (2002):192-201). Upregulation of the NCX can be involved in the induction of AFby the arrhythmogenic activity of the NCX and in its maintenance, andhence NCX blockers have therapeutically favorable effects in the therapyand prevention of AF. Since AF is an increasing disease in the agingpopulation and is frequently associated with heart failure in up toabout 45% of patients (I. Savelieva et al., Europace. 5 Suppl 1 (2004):S5-S19), NCX blockers would be particularly favorable in patients withAF and CHF.

Since NCX blockers also exert a positive inotropic effect in the atria,they may be particularly favorable in diastolic heart failure whereventricular filling is the major problem as a consequence of ventricularstiffening. A more vigorous atrial contraction would improve ventricularfilling in diastolic heart failure.

Since a reduced cardiac output has deleterious effects on the perfusionof organs such as the kidney, brain and heart, inhibition of the NCX,which increases the contractility of the heart, is able to improveperfusion of the brain, heart and kidney for a therapy or prevention ofstroke, dementia and Alzheimer's disease, renal failure and cardiacischemia. Since the NCX is also involved in salt sensitive hypertension,its inhibition is also suited for the treatment of hypertension.

Inhibitors of the NCX are also suited for the therapy and prevention oflife threatening conditions in which ionotropic support is required tomaintain a sufficient level of blood supply. This includes all forms ofshock, hemodynamic shock, cardiogenic shock and septic shock. Inhibitorsof the NCX are particularly suited to treat these conditions becausethey are neutral on heart rate and lack the proarrhythmic or vasodilatoror vasoconstrictor properties of other inotropic drugs.

In stroke, NCX blockers have the potential of improving the outcomesince in neuronal hypoxia, as occurs in stroke, the NCX reverses itstransport direction to reverse mode, and loads the cells with calciumleading to a calcium overload. This leads to accelerated cell death dueto excessive intracellular calcium concentrations. Moreover, a lowcardiac output can lead to brain ischemia favoring stroke. NCX-blockerswill increase cardiac output and raise brain perfusion. Hence.NCX-blockers have a potential in the therapy and prevention of stroke(T. Matsuda et al., J. Pharmacol. Exp. Ther. 298 (2001): 249-2569.

Certain compounds capable of inhibiting the NCX have already beendescribed, e.g. in EP 0978506, JP 2008/189592, WO 2004/000813, WO2004/063191, WO 03/006452, WO 02/32883, WO 97/09306. However, therestill is a need for further compounds which inhibit the NCX and aresuitable for use as pharmaceuticals in the treatment of the mentioneddisease states. It has now been found that the compounds of the formulaI are excellent inhibitors of the sodium-calcium exchanger (NCX),especially of the sodium-calcium exchanger of subtype 1 (NCX1), and havea favorable property profile for such use.

Thus, a subject of the present invention are the compounds of theformula I, in any of their stereoisomeric forms and mixtures ofstereoisomeric forms in any ratio, and the pharmaceutically acceptablesalts thereof,

wherein

-   Ar is selected from the series consisting of phenyl and a 5-membered    or 6-membered monocyclic aromatic heterocycle, which are all    unsubstituted or substituted by one or more identical or different    substituents R1, wherein the heterocycle comprises 1 or 2 identical    or different ring heteroatoms selected from the series consisting of    nitrogen, oxygen and sulfur and is bonded via a ring carbon atom;-   R1 is selected from the series consisting of halogen, (C₁-C₆)-alkyl,    (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, phenyl, Het1,    HO—, (C₁-C₆)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, phenyl-O—, Het1-O— and    (C₁-C₆)-alkyl-S(O)_(n)—, and two groups R1 bonded to adjacent ring    carbon atoms in Ar, together with the carbon atoms carrying them,    can form a 5-membered to 7-membered mono-unsaturated ring which    comprises 0, 1 or 2 identical or different ring heteroatoms selected    from the series consisting of nitrogen, oxygen and sulfur, and which    is unsubstituted or substituted by one or more identical or    different substituents selected from the series consisting of    fluorine and (C₁-C₄)-alkyl;-   R2 is selected from the series consisting of R5-N(R6)-C(O)—,    R5-N(R6)-CH₂—, R7-C(O)—NH—CH₂— and R7-S(O)₂—NH—CH₂—;-   R3 is selected from the series consisting of hydrogen, halogen,    (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—;-   R4 is hydrogen or one or more identical or different substituents    selected from the series consisting of halogen, (C₁-C₄)-alkyl and    (C₁-C₄)-alkyl-O—;-   R5 and R6 are independently of one another selected from the series    consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,    (C₆-C₁₀)-bicycloalkyl, phenyl, Het1 and Het2, wherein (C₁-C₆)-alkyl    is unsubstituted or substituted by one or more identical or    different substituents R10, and (C₃-C₇)-cycloalkyl,    (C₆-C₁₀)-bicycloalkyl and Het2 all are unsubstituted or substituted    by one or more identical or different substituents R11,-   or the groups R5 and R6, together with the nitrogen atom carrying    them, form a 4-membered to 10-membered, monocyclic or bicyclic,    saturated or partially unsaturated heterocycle which, in addition to    the nitrogen atom carrying R5 and R6, comprises 0 or 1 further ring    heteroatom selected from the series consisting of nitrogen, oxygen    and sulfur, and which is unsubstituted or substituted by one or more    identical or different substituents R12;-   R7 is selected from the series consisting of (C₁-C₆)-alkyl,    (C₃-C₇)-cycloalkyl, phenyl, Het2 and Het3, wherein (C₁-C₆)-alkyl,    (C₃-C₇)-cycloalkyl and Het2 all are unsubstituted or substituted by    one or more identical or different substituents R10, and phenyl and    Het3 all are unsubstituted or substituted by one or more identical    or different substituents R13;-   R10 is selected from the series consisting of R14, fluorine, HO—,    oxo, (C₁-C₆)-alkyl-O—R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,    (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, (C₁-C₆)-alkyl-S(O)_(n)—,    R16-N(R17)-, R18-C(O)—N(R17)-, R16-N(R17)-C(O)—, R19-O—C(O)— and    R16-N(R17)-S(O)₂—;-   R11 and R12 are independently of one another selected from the    series consisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,    R16-N(R17)-(C₁-C₄)-alkyl-, R19-O—C(O)—(C₁-C₄)-alkyl-, R14, fluorine,    HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—,    HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—,    (C₁-C₆)-alkyl-S(O)_(n)—, R16-N(R17)-, R18-C(O)—N(R17)-,    R16-N(R17)-C(O)—, R19-O—C(O)— and R16-N(R17)-S(O)₂—;-   R13 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, HO—, (C₁-C₄)-alkyl-O— and R16-N(R17)-, and two    substituents R13 bonded to adjacent ring carbon atoms in R7,    together with the carbon atoms carrying them, can form a 5-membered    to 7-membered mono-unsaturated ring which comprises 0, 1 or 2    identical or different ring heteroatoms selected from the series    consisting of nitrogen, oxygen and sulfur, and which is    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;-   R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring    which is saturated, partially unsaturated or aromatic and comprises    0, 1, 2, 3 or 4 identical or different ring heteroatoms selected    from the series consisting of nitrogen, oxygen and sulfur, and which    is unsubstituted or substituted by one or more identical or    different substituents R20;-   R15 and R18 are independently of one another selected from the    series consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, phenyl-(C₁-C₄)-alkyl- and    Het1-(C₁-C₄)-alkyl-;-   R16 and R17 are independently of one another selected from the    series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, phenyl-(C₁-C₄)-alkyl- and    Het1-(C₁-C₄)-alkyl-,    or the groups R16 and R17, together with the nitrogen atom carrying    them, form a 4-membered to 7-membered, monocyclic saturated    heterocycle which, in addition to the nitrogen atom carrying R16 and    R17, comprises 0 or 1 further ring heteroatom selected from the    series consisting of nitrogen, oxygen and sulfur, and which is    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;-   R19 is selected from the series consisting of hydrogen,    (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, phenyl-(C₁-C₄)-alkyl- and    Het1-(C₁-C₄)-alkyl-;-   R20 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₃-C₇)-cycloalkyl, HO—, oxo,    (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,    (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, (C₁-C₆)-alkyl-S(O)_(n)—,    R16-N(R17)-, R18-C(O)—N(R17)-, R18-O—C(O)—N(R17)-, NC—, R18-C(O)—,    R16-N(R17)-C(O)—, R19-O—C(O)— and R16-N(R17)-S(O)₂—;-   Het1 is a 5-membered or 6-membered monocyclic aromatic heterocycle    comprising 1 or 2 identical or different ring heteroatoms selected    from the series consisting of nitrogen, oxygen and sulfur, which is    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—;-   Het2 is a 4-membered to 10-membered monocyclic or bicyclic,    saturated or partially unsaturated heterocycle comprising 1 or 2    identical or different ring heteroatoms selected from the series    consisting of nitrogen, oxygen and sulfur;-   Het3 is a 5-membered to 10-membered monocyclic or bicyclic aromatic    heterocycle comprising 1 or 2 identical or different ring    heteroatoms selected from the series consisting of nitrogen, oxygen    and sulfur;

n is selected from the series consisting of 0, 1 and 2, wherein allnumbers n are independent of one another;

-   wherein all phenyl groups, unless specified otherwise, are    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl and —O—(C₁-C₄)-alkyl;-   wherein all cycloalkyl and bicycloalkyl groups, independently of any    other substituents which can be present on a cycloalkyl or    bicycloalkyl group, can be substituted by one or more identical    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents.

The groups R2 and R3 in the compounds of the formula I and all othercompounds in which the groups R2 and R3 occur and in the respectiveformulae are not bonded to a specific ring atom, can be bonded to any ofthe two carbons atom of the thiazole ring system depicted in formula Iwhich have a free binding site, i.e. to the carbon atoms in ringpositions 4 and 5 of the thiazole ring system, as is indicated by thebonds originating at R2 and R3 which are not directed to a specificcarbon atom. One of the groups R2 and R3 is bonded to the carbon atom inring position 4 of the thiazole ring system, and the other of the groupsR2 and R3 is bonded to the carbon atom in ring position 5 of thethiazole ring system. This applies accordingly to other groups incompounds referred to herein whose binding position is not fixed intheir formulae, such as the group Y in the compounds of the formulae IIIand IV, for example.

Likewise, groups R4 in the compounds of the formula I and all othercompounds in which groups R4 occur, which are different from hydrogen,can be bonded to any carbon atoms of the chroman ring system depicted informula I which have a free binding site, i.e. to carbon atoms in ringpositions 2, 3, 4, 5, 7 and 8 of the chroman ring system, as isindicated by the bond originating at R4 which is not directed to aspecific carbon atom of the chroman ring. In all free bonding sites ofthe carbons atom in ring positions 2, 3, 4, 5, 7 and 8 of the chromanring system which are not occupied by groups R4 different from hydrogen,hydrogen atoms are present. I.e., if in a compound of the formula I nogroup R4 is present which is different from hydrogen, the carbon atomsin ring positions 2, 5, 7 and 8 of the chroman ring system carry onehydrogen atom, and the carbon atoms in ring positions 3 and 4 of thechroman ring system carry two hydrogen atoms. If substituents R4 arepresent, i.e. atoms or groups representing R4 which are different fromhydrogen, one or more of the said hydrogen atoms are replaced by thesubstituents R4.

If structural elements such as groups, substituents or numbers, forexample, can occur several times in the compounds of the formula I, theyare all independent of each other and can in each case have any of theindicated meanings, and they can in each case be identical to ordifferent from any other such element. In a dialkylamino group, forexample, the alkyl groups can be identical or different.

Alkyl groups, i.e. saturated hydrocarbon residues, can be linear(straight-chain) or branched. This also applies if these groups aresubstituted or are part of another group, for example an alkyl-O— group(alkyloxy group, alkoxy group) or an HO-substituted alkyl group(HO-alkyl-, hydroxyalkyl group). Depending on the respective definition,the number of carbon atoms in an alkyl group can be 1, 2, 3, 4, 5 or 6,or 1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2, or 1. Examples of alkyl aremethyl, ethyl, propyl including n-propyl and isopropyl, butyl includingn-butyl, sec-butyl, isobutyl and tert-butyl, pentyl including n-pentyl,1-methylbutyl, isopentyl, neopentyl and tert-pentyl, and hexyl includingn-hexyl, 3,3-dimethylbutyl and isohexyl. Examples of alkyl-O— groups aremethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentoxy. Examples of alkyl-S(O)_(n)— aremethylsulfanyl-(CH₃—S—), methanesulfinyl-(CH₃—S(O)—), methanesulfonyl(CH₃—S(O)₂—), ethylsulfanyl-(CH₃—CH₂—S—),ethanesulfinyl-(CH₃—CH₂—S(O)—), ethanesulfonyl (CH₃—CH₂—S(O)₂—),1-methylethylsulfanyl-((CH₃)₂CH—S—),1-methylethanesulfinyl-((CH₃)₂CH—S(O)—), 1-methylethanesulfonyl((CH₃)₂CH—S((1)₂—). In one embodiment of the invention, the number n isselected from the series consisting of 0 and 2, wherein all numbers nare independent of each other and can be identical or different. Inanother embodiment the number n in any of its occurrences, independentof its meaning in other occurrences, is 0. In another embodiment thenumber n in any of its occurrences is, independent of its meaning inother occurrences, 2.

A substituted alkyl group can be substituted in any positions, providedthat the respective compound is sufficiently stable and is suitable as apharmaceutical active compound. The prerequisite that a specific groupand a compound of the formula I are sufficiently stable and suitable asa pharmaceutical active compound, applies in general with respect to thedefinitions of all groups in the compounds of the formula I. As examplesof substituted alkyl groups, specifically of HO—(C₁-C₄)-alkyl groups,for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,1-hydroxy-1-methylethyl, 2-hydroxy-1-methylethyl, 1-hydroxybutyl,4-hydroxybutyl, 2-hydroxy-1-methylpropyl or 2-hydroxy-1-methylpropyl maybe mentioned. An alkyl group which, independently of any othersubstituents, can be substituted by one or more fluorine substituents,can be unsubstituted by fluorine substituents, i.e. not carry fluorinesubstituents, or substituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9,10 or 11 fluorine substituents, or by 1, 2, 3, 4 or 5 fluorinesubstituents, or by 1, 2 or 3 fluorine substituents, which can belocated in any positions. For example, in a fluoro-substituted alkylgroup one or more methyl groups can carry three fluorine substituentseach and be present as trifluoromethyl groups, and/or one or moremethylene groups (CH₂) can carry two fluorine substituents each and bepresent as difluoromethylene groups. The explanations with respect tothe substitution of a group by fluorine also apply if the groupadditionally carries other substituents and/or is part of another group,for example of an alkyl-O— group. Examples of fluoro-substituted alkylgroups are trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl,1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyland heptafluoroisopropyl. Examples of fluoro-substituted alkyl-O— groupsare trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and3,3,3-trifluoropropoxy. Examples of fluoro-substituted alkyl-S(O)_(n)—groups are trifluoromethylsulfanyl-(CF₃—S—),trifluoromethanesulfinyl-(CF₃—S(O)—) and trifluoromethanesulfonyl(CF₃—S((1)₂—). With respect to all groups or substituents in thecompounds of the formula I which can be an alkyl group which cangenerally contain one or more fluorine substituents, as an example ofgroups or substituents containing fluorine-substituted alkyl which maybe included in the definition of the group or substituent, the group CF₃(trifluoromethyl), or respective groups such as CF₃—O— or CF₃—S—, may bementioned.

The above explanations with respect to alkyl groups applycorrespondingly to alkyl groups which in the definition of a group inthe compounds of the formula I are bonded to two adjacent groups, orlinked to two groups, and may be regarded as divalent alkyl groups(alkanediyl groups), like in the case of the alkyl part of a substitutedalkyl group. Thus, such groups can also be linear or branched, the bondsto the adjacent groups can be located in any positions and can startfrom the same carbon atom or from different carbon atoms, and they canbe unsubstituted or substituted by fluorine substituents independentlyof any other substituents. Examples of such divalent alkyl groups are—CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —CH(CH₃)—,—C(CH₃)₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂—, —CH₂—C(CH₃)₂—.Examples of fluoro-substituted alkanediyl groups, which can contain 1,2, 3, 4, 5 or 6 fluorine substituents, for example, are —CHF—, —CF₂—,—CF₂—CH₂—, —CH₂—CF₂—, —CF₂—CF₂—, —CF(CH₃)—, —C(CF₃)₂, —C(CH₃)₂—CF₂—,—CF₂—C(CH₃)₂—.

The number of ring carbon atoms in a (C₃-C₇)-cycloalkyl group can be 3,4, 5, 6 or 7. Examples of cycloalkyl are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. The number of ring carbon atomsin a (C₆-C₁₀)-bicycloalkyl group can be 6, 7, 8, 9 or 10. The two cyclesin a bicycloalkyl group can have one, two to more ring carbon atoms incommon and can be fused or form a bridged bicycle or a spirocycle.Examples of bicycloalkyl are bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[3.2.2]nonyl and bicyclo[4,4.0]decyl. Bicycloalkyl groups can bebonded via any ring carbon atom. Cycloalkyl and bicycloalkyl groupswhich, independently of any other substituents, can be substituted byone or more (C₁-C₄)-alkyl substituents, can be unsubstituted by alkylsubstituents, i.e. not carry alkyl substituents, or substituted, forexample by 1, 2, 3 or 4 identical or different (C₁-C₄)-alkylsubstituents, for example by methyl groups, which substituents can belocated in any positions. Examples of such alkyl-substituted cycloalkylgroups and bicycloalkyl groups are 1-methylcyclopropyl,2,2-dimethylcyclopropyl, 1-methylcyclopentyl, 2,3-dimethylcyclopentyl,1-methylcyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl,4-tert-butylcyclohexyl, 3,3,5,5-tetramethylcyclohexyl,7,7-dimethylbicyclo[2.2.1]heptyl, 6,6-dimethylbicyclo[3.1.1]heptyl and1,7,7-trimethylbicyclo[2.2.1]heptyl. Cycloalkyl groups and bicycloalkylgroups which, independently of any other substituents, can besubstituted by one or more fluorine substituents, can be unsubstitutedby fluorine substituents, i.e. not carry fluorine substituents, orsubstituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 fluorinesubstituents, or by 1, 2, 3, 4, 5 or 6 fluorine substituents, or by 1, 2or 3 fluorine substituents. The fluorine substituents can be located inany positions of the cycloalkyl group or bicycloalkyl groups and canalso be located in an alkyl substituent. Examples of fluoro-substitutedcycloalkyl groups and bicycloalkyl groups are 1-fluorocyclopropyl,2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, 1-fluorocyclohexyl,4,4-difluorocyclohexyl, 3,3,4,4,5,5-hexafluorocyclohexyl,1-fluorobicyclo[2.2.2]octyl and 1,4-difluorobicyclo[2.2.2]octyl.Cycloalkyl groups can also be substituted simultaneously by fluorine andalkyl. Examples of the group (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl- arecyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-,cyclohexylmethyl-, cycloheptylmethyl-, 1-cyclopropylethyl-,2-cyclopropylethyl-, 1-cyclobutylethyl-, 2-cyclobutylethyl-,1-cyclopentylethyl-, 2-cyclopentylethyl-, 1-cyclohexylethyl-,2-cyclohexylethyl-, 1-cycloheptylethyl-, 2-cycloheptylethyl-. In oneembodiment of the invention, a (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl- groupin any one or more occurrences of such a group, independently of anyother occurrences, is a (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl- group, inanother embodiment a (C₃-C₇)-cycloalkyl-CH₂— group. In the group(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, and likewise in all other groups, theterminal hyphen denotes the free bond via the group is bonded, and thusindicates via which subgroup a group composed of subgroups is bonded.

In substituted phenyl groups, including phenyl groups representing Arand R14, the substituents can be located in any positions. Inmonosubstituted phenyl groups, the substituent can be located inposition 2, in position 3 or in position 4. In disubstituted phenylgroups, the substituents can be located in positions 2 and 3, inpositions 2 and 4, in positions 2 and 5, in positions 2 and 6, inpositions 3 and 4, or in positions 3 and 5. In trisubstituted phenylgroups, the substituents can be located in positions 2, 3 and 4, inpositions 2, 3 and 5, in positions 2, 3 and 6, in positions 2, 4 and 5,in positions 2, 4 and 6, or in positions 3, 4 and 5. If a phenyl groupcarries four substituents, some of which can be fluorine atoms, forexample, the substituents can be located in positions 2, 3, 4 and 5, inpositions 2, 3, 4 and 6, or in positions 2, 3, 5 and 6. If apolysubstituted phenyl group or any other polysubstituted group carriesdifferent substituents, each substituent can be located in any suitableposition, and the present invention comprises all positional isomers.The number of substituents in a substituted phenyl group can be 1, 2, 3,4 or 5. In one embodiment of the invention, the number of substituentsin a substituted phenyl group, like the number of substituents in anyother substituted group which can carry one or more substituents, is 1,2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or2, in another embodiment 1, where the number of substituents in anyoccurrence of such a substituted group is independent of the number ofsubstituents in other occurrences.

In heterocyclic groups, including the groups Het1, Het2 and Het3,heterocycles representing Ar and R14 and other heterocyclic rings whichcan be present in the compounds of the formula I, such as rings formedby two group together with the atom or atoms carrying them, the heteroring members can be present in any combination and located in anysuitable ring positions, provided that the resulting group and thecompound of the formula I are suitable and sufficiently stable as apharmaceutical active compound. In one embodiment of the invention, twooxygen atoms in any heterocyclic ring in the compounds of the formula Icannot be present in adjacent ring positions. In another embodiment ofthe invention, two hetero ring members selected from the seriesconsisting of oxygen atoms and sulfur atoms cannot be present inadjacent ring positions in any heterocyclic ring in the compounds of theformula I. In another embodiment of the invention, two hetero ringmembers selected from the series consisting of nitrogen atoms carryingan exocyclic group like a hydrogen atom or a substituent, sulfur atomsand oxygen atoms cannot be present in adjacent ring positions in anyheterocyclic ring in the compounds of the formula I. In an aromaticheterocyclic ring the choice of hetero ring members is limited by theprerequisite that the ring is aromatic, i.e. it comprises a cyclicsystem of six delocalized pi electrons. Monocyclic aromatic heterocyclesare 5-membered or 6-membered rings and, in the case of a 5-memberedring, comprise one ring heteroatom selected from the series consistingof oxygen, sulfur and nitrogen, wherein this ring nitrogen carries anexocyclic group like a hydrogen atom or a substituent, and optionallyone or more further ring nitrogen atoms, and, in the case of a6-membered ring, comprise one or more nitrogen atoms as ringheteroatoms, but no oxygen atoms and sulfur atoms as ring heteroatoms.Unless specified otherwise in the definition of the group, heterocyclicgroups can be bonded via any suitable ring atom, i.e. any ring atomwhich carries a hydrogen atom or a substituent, including ring carbonatoms and ring nitrogen atoms. In one embodiment of the invention, anyof the heterocyclic groups occurring in the compounds of the formula Iin any of its occurrences, is independently of its other occurrences andindependently of any other heterocyclic group, bonded via a ring carbonatom, and in another embodiment via a ring nitrogen atom, if applicable.In substituted heterocyclic groups, the substituents can be located inany positions.

The number of ring heteroatoms which can be present in a heterocyclicgroup in the compounds of the formula I, the number of cycles, i.e.whether the heterocyclic group can be monocyclic and/or bicyclic, thenumber of ring members which can be present, and the degree ofsaturation, i.e. whether the heterocyclic group is saturated and doesnot contain a double bond within the ring, or whether it is partiallyunsaturated and contains one or more, for example one or two, doublebonds within the ring but is not aromatic, or whether it is aromatic andthus contains two double bonds within the ring in the case of a5-membered monocyclic aromatic heterocycle, three double bonds withinthe ring in the case of a 6-membered monocyclic aromatic heterocycle,four double bonds within the ring in the case of 9-membered bicyclicaromatic heterocycle, and five double bonds within the ring in the caseof 10-membered aromatic heterocycle, is specified in the definitions ofthe individual groups in the compounds of the formula I. The two cyclesin a bicyclic heterocyclic group can have one, two or more ring atoms incommon and can be fused or form a bridged bicycle or a spirocycle. Asexamples of heterocyclic ring systems, from which heterocyclic groups inthe compounds of the formula I can be derived, and from any one or moreof which any of the heterocyclic groups in the compounds of the formulaI is selected in one embodiment of the invention, provided that the ringsystem is comprised by the definition of the group, oxetane, thietane,azetidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene,pyrrole, pyrroline, pyrrolidine, 1,3-dioxole, 1,3-dioxolane, isoxazole([1,2]oxazole), isoxazoline, isoxazolidine, oxazole ([1,3]oxazole),oxazoline, oxazolidine, isothiazole ([1,2]thiazole), isothiazoline,isothiazolidine, thiazole ([1,3]thiazole), thiazoline, thiazolidine,pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline,imidazolidine, [1,2,3]triazole, [1,2,4]triazole, [1,2,4]oxadiazole,[1,3,4]oxadiazole, 1,2,5-oxadiazole, [1,2,4]thiadiazole, 1H-tetrazole,pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran,2,3-dihydro[1,4]dioxine, 1,4-dioxane, pyridine,1,2,5,6-tetrahydropyridine, piperidine, morpholine, thiomorpholine,piperazine, pyridazine, pyrimidine, pyrazine, [1,2,4]triazine, oxepane,thiepane, azepane, [1,3]diazepane, [1,4]diazepane, [1,4]oxazepane,[1,4]thiazepanel, azocane, 3-azabicyclo[3.1.0]hexane,octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole,2-azaspiro[4.4]nonane, 7-azabicyclo[2.2.1]heptane,2,7-diazaspiro[4.4]nonane, octahydropyrrolo[3,4-b]pyrrole,6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole, imidazo[2,1-b]thiazole,6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine, benzofuran, isobenzofuran,benzothiophene (benzo[b]thiophene), 1H-indole, 2,3-dihydro-1H-indole,octahydroindole, 2H-isoindole, octahydroisoindole, benzo[1,3]dioxole,benzoxazole, benzthiazole, 1H-benzimidazole, imidazo[1,2-a]pyridine,[1,2,4]triazolo[4,3-a]pyridine, chroman, isochroman, thiochroman,benzo[1,4]dioxane, 3,4-dihydro-2H-benzo[1,4]oxazine,3,4-dihydro-2H-benzo[1,4]thiazine, 2-azaspiro[4.5]decane,3-azabicyclo[3.2.2]nonane, quinoline, 1,2,3,4-tetrahydroquinoline,5,6,7,8-tetrahydroquinoline, isoquinoline, 1,2,3,4,-tetrahydroisoquinoline, 5,6,7,8-tetrahydroisoquinoline,2,7-diazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, cinnoline,quinazoline, quinoxaline, phthalazine and [1,8]naphthyridine may bementioned, which can all be unsubstituted or substituted in any suitablepositions as specified in the definition of the respective group in thecompounds of the formula I, wherein the given degree of unsaturation inby way of example only, and in the individual groups also ring systemswith a higher or lower degree of saturation, or hydrogenation, or ofunsaturation can be present as specified in the definition of the group.

As mentioned, the heterocyclic groups can be bonded via any suitablering atom. For example, among others can an oxetane and a thietane ringbe bonded via positions 2 and 3, an azetidine ring via positions 1, 2and 3, a furan ring, a tetrahydrofuran ring, a thiophene ring and atetrahydrothiophene via positions 2 and 3, a pyrrole ring and apyrrolidine ring via positions 1, 2 and 3, an isoxazole ring and anisothiazole ring via positions 3, 4 and 5, a pyrazole ring via positions1, 3, 4 and 5, an oxazole ring and a thiazole ring via positions 2, 4and 5, an imidazole ring and an imidazolidine ring via positions 1, 2, 4and 5, a 1H-tetrazole ring via positions 1 and 3, a tetrahydropyran anda tetrahydrothiopyran ring via positions 2, 3 and 4, a 1,4-dioxane ringvia position 2, a pyridine ring via positions 2, 3 and 4, a piperidinering via positions 1, 2, 3 and 4, a morpholine ring and a thiomorpholinering via positions 2, 3 and 4, a piperazine ring via positions 1 and 2,a pyrimidine ring via positions 2, 4 and 5, a pyrazine ring via position2, an azepane ring via positions 1, 2, 3 and 4, a3-azabicyclo[3.1.0]hexane ring via positions 3 and 6, anoctahydrocyclopenta[b]pyrrole and an octahydrocyclopenta[c]pyrrole ringvia position 1, a 2-azaspiro[4.4]nonane ring via position 2, a7-azabicyclo[2.2.1]heptane ring via position 7, anoctahydropyrrolo[3,4-b]pyrrole ring via positions 1 and 5, a6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole ring via position 3, animidazo[2,1-b]thiazole ring via positions 2, 5 and 6, a6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine via position 3, a benzofuranring and a benzothiophene ring via positions 2, 3, 4, 5, 6 and 7, a1H-indole ring, a 2,3-dihydro-1H-indole and an octahydroindole ring viapositions 1, 2, 3, 4, 5, 6 and 7, a benzo[1,3]dioxole ring via positions4, 5, 6 and 7, a benzoxazole ring and a benzthiazole ring via positions2, 4, 5, 6 and 7, a 1H-benzimidazole ring via positions 1, 2, 4, 5, 6and 7, an imidazo[1,2-a]pyridine ring via positions 2 and 3, a[1,2,4]triazolo[4,3-a]pyridine ring via position 3, a benzo[1,4]dioxanering via positions 5, 6, 7 and 8, a 3-azabicyclo[3.2.2]nonane ring viaposition 3, a quinoline ring via positions 2, 3, 4, 5, 6, 7 and 8, a1,2,3,4-tetrahydroquinoline ring via positions 1, 5, 6, 7 and 8, a5,6,7,8-tetrahydroquinoline via positions 2, 3 and 4, an isoquinolinering via positions 1, 3, 4, 5, 6, 7 and 8, a1,2,3,4-tetrahydroisoquinoline ring via positions 2, 5, 6, 7 and 8, a5,6,7,8-tetrahydroisoquinoline ring via positions 1, 3, 4 and 5, a2,7-diazaspiro[4.5]decane ring via positions 2 and 7, a2,8-diazaspiro[4.5]decane ring via positions 2 and 8, for example,wherein the resulting residues of the heterocyclic groups can all beunsubstituted or substituted in any suitable positions as specified inthe definition of the respective group in the compounds of the formulaI.

Halogen is fluorine, chlorine, bromine or iodine. In one embodiment ofthe invention, in any of its occurrences halogen is fluorine, chlorineor bromine, in another embodiment fluorine or chlorine, in anotherembodiment fluorine, in another embodiment chorine, where alloccurrences of halogen are independent of each other.

An oxo group, i.e. a doubly bonded oxygen atom, when bonded to a carbonatom, replaces two hydrogen atoms on a carbon atom of the parent system.Thus, if a CH₂ group is substituted by oxo, it becomes a carbonyl group(C(O), C═O). Oxo groups can also occur on sulfur atoms, such as on ringsulfur atoms in saturated and partially unsaturated heterocycles inwhich generally, besides a ring sulfur atom, also an S(O) group (S(═O))and an S(O)₂ group (S(═O)₂) can be present as hetero ring members. Anoxo group cannot occur as a substituent on a carbon atom in an aromaticring such as in a phenyl group.

The present invention comprises all stereoisomeric forms of thecompounds of the formula I, for example all enantiomers anddiastereomers including cis/trans isomers. The invention likewisecomprises mixtures of two or more stereoisomeric forms, for examplemixtures of enantiomers and/or diastereomers including cis/transisomers, in all ratios. Asymmetric centers contained in the compounds ofthe formula I, for example the carbon atom in position 2 of the chromanring system or in unsubstituted or substituted alkyl groups, can allindependently of each other have S configuration or R configuration. Theinvention relates to enantiomers, both the levorotatory and thedextrorotatory antipode, in enantiomerically pure form and essentiallyenantiomerically pure form, for example with a molar ratio of the twoenantiomers of 98:2, or 99:1, or greater, and in the form of theirracemate, i.e. a mixture of the two enantiomers in molar ratio of 1:1,and in the form of mixtures of the two enantiomers in all ratios. Theinvention likewise relates to diastereomers in the form of pure andessentially pure diastereomers and in the form of mixtures of two ormore diastereomers in all ratios. The invention also comprises allcis/trans isomers of the compounds of the formula I in pure form andessentially pure form, for example with a molar ratio of the cis/transisomers of 98:2, or 99:1, or greater, and in the form of mixtures of thecis isomer and the trans isomer in all ratios. Cis/trans isomerism canoccur in substituted rings. The preparation of individual stereoisomers,if desired, can be carried out by resolution of a mixture according tocustomary methods, for example, by chromatography or crystallization, orby use of stereochemically uniform starting compounds in the synthesis,or by stereoselective reactions. Optionally, before a separation ofstereoisomers a derivatization can be carried out. The separation of amixture of stereoisomers can be carried out at the stage of the compoundof the formula I or at the stage of an intermediate in the course of thesynthesis. For example, in the case of a compound of the formula Icontaining an asymmetric center the individual enantiomers can beprepared by preparing the racemate of the compound of the formula I andresolving it into the enantiomers by high pressure liquid chromatographyon a chiral phase according to standard procedures, or resolving theracemate of any intermediate in the course of its synthesis by suchchromatography or by crystallization of a salt thereof with an opticallyactive amine or acid and converting the enantiomers of the intermediateinto the enantiomeric forms of the final compound of the formula or byperforming an enantioselective reaction in the course of the synthesis.The invention also comprises all tautomeric forms of the compounds ofthe formula I.

If the compounds of the formula I comprise one or more acidic or basicgroups for example basic heterocyclic groups, the correspondingphysiologically or toxicologically acceptable salts are also included inthe invention, especially the pharmaceutically acceptable salts. Thecompounds of the formula I may thus be deprotonated on an acidic groupand be used for example as alkali metal salts, for example sodium orpotassium salts, or as ammonium salts, for example as salts with ammoniaor organic amines or amino acids. Compounds of the formula I comprisingat least one basic group may also be prepared and used in the form oftheir acid addition salts, for example in the form of pharmaceuticallyacceptable salts with inorganic acids and organic acids, such as saltswith hydrochloric acid and thus be present in the form of thehydrochlorides, for example. Salts can in general be prepared fromacidic and basic compounds of the formula I by reaction with an acid orbase in a solvent or diluent according to customary procedures. If thecompounds of the formula I simultaneously contain an acidic and a basicgroup in the molecule, the invention also includes internal salts(betaines, zwitterions) in addition to the salt forms mentioned. Thepresent invention also comprises all salts of the compounds of theformula I which, because of low physiological tolerability, are notdirectly suitable for use as a pharmaceutical, but are suitable asintermediates for chemical reactions or for the preparation ofphysiologically acceptable salts, for example by means of anion exchangeor cation exchange.

In one embodiment of the invention, an aromatic heterocycle representingthe group Ar comprises 1 or 2 identical or different ring heteroatomswhich are selected from the series consisting of nitrogen and sulfur. Inanother embodiment, an aromatic heterocycle representing Ar is a5-membered heterocycle which comprises 1 or 2 identical or differentring heteroatoms which are selected from the series consisting ofnitrogen and sulfur, in another embodiment 1 ring heteroatom which is asulfur atom, or it is a 6-membered heterocycle which comprises 1 or 2ring heteroatoms which are nitrogen atoms. In another embodiment, anaromatic heterocycle representing Ar is selected from the seriesconsisting of thiophene, thiazole, pyridine, pyridazine, pyrimidine andpyrazine, in another embodiment from the series consisting of thiophene,pyridine, pyridazine, pyrimidine and pyrazine, in another embodimentfrom the series consisting of thiophene, pyridine, pyrimidine andpyrazine, in another embodiment from the series consisting of thiophene,pyridine and pyrazine, in another embodiment from the series consistingof pyridine and pyrazine, in another embodiment from the seriesconsisting of thiophene and pyridine, in another embodiment it isthiophene, and in another embodiment is pyridine, which heterocycles areall unsubstituted or substituted as indicated. In one embodiment of theinvention, Ar is phenyl which is unsubstituted or substituted by one ormore identical or different substituents R1, in another embodiment Ar isa 5-membered or 6-membered aromatic heterocycle which is unsubstitutedor substituted by one or more identical or different substituents R1. Inone embodiment of the invention, the number of substituents R1 which canbe present in the group Ar is 1, 2 or 3, in another embodiment it is 1or 2, in another embodiment it is 1.

The double bond which is present in the mono-unsaturated ring which canbe formed by two substituents R1 bonded to adjacent ring carbon atoms inAr together with the carbon atoms carrying them, is present between thesaid two adjacent ring carbon in the aromatic ring Ar which are commonto the ring Ar and the ring formed by the two groups R1, and because ofthe rules of nomenclature for fused rings is regarded as a double bondpresent in both rings. The case that two groups R1 bonded to adjacentcarbon atoms in Ar together with the carbon atoms carrying them form a5-membered to 7-membered mono-unsaturated ring, can in other terms beregarded as two groups R1 together forming a divalent residue comprisinga chain of 3 to 5 atoms of which 0, 1 or 2 are identical or differentheteroatoms selected from the series consisting of nitrogen, oxygen andsulfur, the terminal atoms of which, which are bonded to the twoadjacent ring carbon atoms in Ar, are separated from each other by 1 to3 atoms. Examples of such divalent residues, from any one or more ofwhich two groups R1 bonded to adjacent ring carbon atoms in Ar areselected in one embodiment of the invention, are the residues—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂—, —O—CH₂—CH₂—, —CH₂—CH₂—O—,—O—CH₂—O—, —O—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—O—, —NH—CH₂—CH₂—O—,—O—CH₂—CH₂—NH—, —S—CH₂—CH₂—NH— and —NH—CH₂—CH₂—S—, which can all besubstituted on carbon atoms and nitrogen atoms by substituents selectedfrom the series consisting of fluorine and (C₁-C₄)-alkyl, for examplefluorine and methyl, and can thus also be present, for example, as thedivalent residues —O—CF₂—O—, —O—C(CH₃)₂—O—, —N(CH₃)—CH₂—CH₂—O—,—O—CH₂—CH₂—N(CH₃)—, —S—CH₂—CH₂—N(CH₃)— and —N(CH₃)—CH₂—CH₂—S—. In oneembodiment of the invention, the ring which can be formed by two groupsR1 bonded to adjacent ring carbon atoms in Ar together with the carbonatoms carrying them, is a 5-membered or 6-membered, in anotherembodiment a 5-membered, in another embodiment a 6-membered ring. In oneembodiment of the invention, the number of substituents selected fromthe series consisting of fluorine and (C₁-C₄)-alkyl, which can bepresent in a ring formed by two groups R1 bonded to adjacent ring carbonatoms in Ar together with the carbon atoms carrying them, is 1, 2 or 3,in another embodiment 1 or 2, in another embodiment 1. In one embodimentof the invention, substituents which can be present in a ring formed bytwo groups R1 bonded to adjacent ring carbon atoms in Ar together withthe carbon atoms carrying them, are fluorine substituents, and inanother embodiment they are (C₁-C₄)-alkyl substituents, for examplemethyl substituents, and in another embodiment are substituents in sucha ring bonded to a ring nitrogen atom selected from the seriesconsisting of (C₁-C₄)-alkyl.

In one embodiment of the invention, R1 is selected from the seriesconsisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, HO—, (C₁-C₆)-alkyl-O—,(C₃-C₇)-cycloalkyl-O— and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, inanother embodiment from the series consisting of halogen, (C₁-C₆)-alkyl,HO— and (C₁-C₆)-alkyl-O—, in another embodiment from the seriesconsisting of halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkyl-O—, in anotherembodiment from the series consisting of halogen and (C₁-C₆)-alkyl, inanother embodiment from the series consisting of halogen, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl, in anotherembodiment from the series consisting of halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, HO—,(C₁-C₆)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O— and (C₁-C₆)-alkyl-S(O)—, in anotherembodiment from the series consisting of halogen, (C₁-C₆)-alkyl, HO—,(C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S(O)_(n)—, in another embodiment fromthe series consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O— and(C₁-C₆)-alkyl-S(O)_(n)—, and in all these embodiment two groups R1bonded to adjacent carbon atoms in Ar, together with the carbon atomscarrying them, can form a 5-membered to 7-membered mono-unsaturated ringwhich comprises 0, 1 or 2 identical or different ring heteroatomsselected from the series consisting of nitrogen, oxygen and sulfur, andwhich is unsubstituted or substituted by one or more identical ordifferent substituents selected from the series consisting of fluorineand (C₁-C₄)-alkyl. In another embodiment, R1 is selected from the seriesconsisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, phenyl, Het1, HO—, (C₁-C₆)-alkyl-O—,(C₃-C₇)-cycloalkyl-O—, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, phenyl-O—,Het1-O— and (C₁-C₆)-alkyl-S(O)—, in another embodiment from the seriesconsisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, HO—, (C₁-C₆)-alkyl-O—,(C₃-C₇)-cycloalkyl-O— and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, inanother embodiment from the series consisting of halogen, (C₁-C₆)-alkyl.HO— and (C₁-C₆)-alkyl-O—, in another embodiment from the seriesconsisting of halogen, (C₁-C₆)-alkyl and (C₁-C₆)-alkyl-O—, in anotherembodiment from the series consisting of halogen and (C₁-C₆)-alkyl, inanother embodiment from the series consisting of halogen, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl, in anotherembodiment from the series consisting of halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, HO—,(C₁-C₆)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O— and (C₁-C₆)-alkyl-S(O)—, in anotherembodiment from the series consisting of halogen, (C₁-C₆)-alkyl, HO—,(C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S(O)—, in another embodiment from theseries consisting of halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O— and(C₁-C₆)-alkyl-S(O)—. In one embodiment, substituents R1 which are bondedto a ring nitrogen atom in Ar, such as in the case of a pyrrole,pyrazole or imidazole ring representing Ar, are selected from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, phenyl and Het1, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl.

In one embodiment of the invention, a (C₁-C₆)-alkyl group whichrepresents R1 or is present in the groups (C₁-C₆)-alkyl-O— and(C₁-C₆)-alkyl-S(O)— representing R1, is a (C₁-C₄)-alkyl group, inanother embodiment a (C₁-C₃)-alkyl group, in another embodiment a(C₁-C₂)-alkyl group, in another embodiment a methyl group. In oneembodiment of the invention, a (C₃-C₇)-cycloalkyl group which representsR1 or is present in R1, is a (C₃-C₆)-cycloalkyl group, in anotherembodiment a (C₃-C₄)-cycloalkyl group, in another embodiment acyclopropyl group.

Examples of groups Ar including the optional substituents R1, from anyone or more of which Ar is selected in one embodiment of the invention,are phenyl, i.e. unsubstituted phenyl, thiophen-2-yl, thiophen-3-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 2-fluoro-phenyl,3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl,4-chloro-phenyl, 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m-tolyl),4-methyl-phenyl (p-tolyl), 2-ethyl-phenyl, 3-ethyl-phenyl,4-ethyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl,2-ethoxy-phenyl, 3-ethoxy-phenyl, 4-ethoxy-phenyl, 2-propoxy-phenyl,3-propoxy-phenyl, 4-propoxy-phenyl, 2-isopropoxy-phenyl,3-isopropoxy-phenyl, 4-isopropoxy-phenyl, 2,3-difluoro-phenyl,2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl,3,4-difluoro-phenyl, 3,5-difluoro-phenyl, 2,3-dichloro-phenyl,2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-dichloro-phenyl,3,4-dichloro-phenyl, 3,5-dichloro-phenyl, 2-chloro-3-fluoro-phenyl,2-chloro-4-fluoro-phenyl, 2-chloro-5-fluoro-phenyl,2-chloro-6-fluoro-phenyl, 3-chloro-2-fluoro-phenyl,3-chloro-4-fluoro-phenyl, 3-chloro-5-fluoro-phenyl,4-chloro-2-fluoro-phenyl, 4-chloro-3-fluoro-phenyl,5-chloro-2-fluoro-phenyl, 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl,2,5-dimethyl-phenyl, 2,6-dimethyl-phenyl, 3,4-dimethyl-phenyl,3,5-dimethyl-phenyl, 2-fluoro-3-methyl-phenyl, 2-fluoro-4-methyl-phenyl,2-fluoro-5-methyl-phenyl, 2-fluoro-6-methyl-phenyl,3-fluoro-2-methyl-phenyl, 3-fluoro-4-methyl-phenyl,3-fluoro-5-methyl-phenyl, 4-fluoro-2-methyl-phenyl,4-fluoro-3-methyl-phenyl, 5-fluoro-2-methyl-phenyl,2-chloro-3-methyl-phenyl, 2-chloro-4-methyl-phenyl,2-chloro-5-methyl-phenyl, 2-chloro-6-methyl-phenyl,3-chloro-2-methyl-phenyl, 3-chloro-4-methyl-phenyl,3-chloro-5-methyl-phenyl, 4-chloro-2-methyl-phenyl,4-chloro-3-methyl-phenyl, 5-chloro-2-methyl-phenyl,2-fluoro-3-methoxy-phenyl, 2-fluoro-4-methoxy-phenyl,2-fluoro-5-methoxy-phenyl, 2-fluoro-6-methoxy-phenyl,3-fluoro-2-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl,3-fluoro-5-methoxy-phenyl, 4-fluoro-2-methoxy-phenyl,4-fluoro-3-methoxy-phenyl, 5-fluoro-2-methoxy-phenyl,2-methoxy-3-methyl-phenyl, 2-methoxy-4-methyl-phenyl,2-methoxy-5-methyl-phenyl, 2-methoxy-6-methyl-phenyl,3-methoxy-2-methyl-phenyl, 3-methoxy-4-methyl-phenyl,3-methoxy-5-methyl-phenyl, 4-methoxy-2-methyl-phenyl,4-methoxy-3-methyl-phenyl, 5-methoxy-2-methyl-phenyl,3-fluoro-thiophen-2-yl, 4-fluoro-thiophen-2-yl, 5-fluoro-thiophen-2-yl,2-fluoro-thiophen-3-yl, 4-fluoro-thiophen-3-yl, 5-fluoro-thiophen-3-yl,3-chloro-thiophen-2-yl, 4-chloro-thiophen-2-yl, 5-chloro-thiophen-2-yl,2-chloro-thiophen-3-yl, 4-chloro-thiophen-3-yl, 5-chloro-thiophen-3-yl,3-methyl-thiophen-2-yl, 4-methyl-thiophen-2-yl, 5-methyl-thiophen-2-yl,2-methyl-thiophen-3-yl, 4-methyl-thiophen-3-yl, 5-methyl-thiophen-3-yl,3-fluoro-pyridin-2-yl, 4-fluoro-pyridin-2-yl, 5-fluoro-pyridin-2-yl,6-fluoro-pyridin-2-yl, 2-fluoro-pyridin-3-yl, 4-fluoro-pyridin-3-yl,5-fluoro-pyridin-3-yl, 6-fluoro-pyridin-3-yl, 2-fluoro-pyridin-4-yl,3-fluoro-pyridin-4-yl, 3-chloro-pyridin-2-yl, 4-chloro-pyridin-2-yl,5-chloro-pyridin-2-yl, 6-chloro-pyridin-2-yl, 2-chloro-pyridin-3-yl,4-chloro-pyridin-3-yl, 5-chloro-pyridin-3-yl, 6-chloro-pyridin-3-yl,2-chloro-pyridin-4-yl, 3-chloro-pyridin-4-yl, 3-methyl-pyridin-2-yl,4-methyl-pyridin-2-yl, 5-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl,2-methyl-pyridin-3-yl, 4-methyl-pyridin-3-yl, 5-methyl-pyridin-3-yl,6-methyl-pyridin-3-yl, 2-methyl-pyridin-4-yl, 3-methyl-pyridin-4-yl,3-methoxy-pyridin-2-yl, 4-methoxy-pyridin-2-yl, 5-methoxy-pyridin-2-yl,6-methoxy-pyridin-2-yl, 2-methoxy-pyridin-3-yl, 4-methoxy-pyridin-3-yl,5-methoxy-pyridin-3-yl, 6-methoxy-pyridin-3-yl, 2-methoxy-pyridin-4-yl,3-methoxy-pyridin-4-yl.

In one embodiment of the invention, the group R2 is selected from theseries consisting of R5-N(R6)-C(O)— and R5-N(R6)-CH₂—, and in anotherembodiment from the series consisting of R7-C(O)—NH—CH₂— andR7-S(O)₂—NH—CH₂—. In another embodiment of the invention, the group R2is the group R5-N(R6)-C(O)—, and respective compounds are designated ascompounds of the formula Ia. In another embodiment of the invention, thegroup R2 is the group R5-N(R6)-CH₂—, and respective compounds aredesignated as compounds of the formula Ib. In another embodiment of theinvention, the group R2 is the group R7-C(O)—NH—CH₂—, and respectivecompounds are designated as compounds of the formula Ic. In anotherembodiment of the invention, the group R2 is the group R7-S(O)₂—NH—CH₂—,and respective compounds are designated as compounds of the formula Id.

The groups Ar, R3, R4, R5, R6 and R7 in the compounds of the formulaeIa, Ib, Ic and Id are defined as in the compounds of the formula I,

In one embodiment of the invention, the group R2 is bonded in ringposition 5 of the thiazole ring system and the group R3 is bonded inposition 4 of the thiazole ring system, and respective compounds aredesignated as compounds of the formula Ie. In another embodiment of theinvention, the group R3 is bonded in ring position 5 of the thiazolering system and the group R2 is bonded in position 4 of the thiazolering system, and respective compounds are designated as compounds of theformula If.

The groups Ar, R2, R3 and R4 in the compounds of the formulae Ie and Ifare defined as in the compounds of the formula I.

In one embodiment of the invention, the group R2 is bonded in ringposition 5 of the thiazole ring system and the group R3 is bonded inposition 4 of the thiazole ring system, and the group R2 is selectedfrom the series consisting of R5-N(R6)-C(O)— and R5-N(R6)-CH₂—, and inanother embodiment from the series consisting of R7-C(O)—NH—CH₂— andR7-S(O)₂—NH—CH₂—. In another embodiment of the invention, the group R2is bonded in ring position 4 of the thiazole ring system and the groupR3 is bonded in position 5 of the thiazole ring system, and the group R2is selected from the series consisting of R5-N(R6)-C(O)— andR5-N(R6)-CH₂—, and in another embodiment from the series consisting ofR7-C(O)—NH—CH₂— and R7-S(O)₂—NH—CH₂—. In another embodiment of theinvention, the group R2 is bonded in ring position 5 of the thiazolering system and is the group R5-N(R6)-C(O)—, and the group R3 is bondedin ring position 4 of the thiazole ring system, and respective compoundsare designated as compounds of the formula Ig. In another embodiment ofthe invention, the group R2 is bonded in ring position 5 of the thiazolering system and is the group R5-N(R6)-CH₂—, and the group R3 is bondedin ring position 4 of the thiazole ring system, and respective compoundsare designated as compounds of the formula Ih. In another embodiment ofthe invention, the group R2 is bonded in ring position 5 of the thiazolering system and is the group R7-C(O)—NH—CH₂—, and the group R3 is bondedin ring position 4 of the thiazole ring system, and respective compoundsare designated as compounds of the formula Ij. In another embodiment ofthe invention, the group R2 is bonded in ring position 5 of the thiazolering system and is the group R7-S(O)₂—NH—CH₂—, and the group R3 isbonded in ring position 4 of the thiazole ring system, and respectivecompounds are designated as compounds of the formula Ik. In anotherembodiment of the invention, the group R2 is bonded in ring position 4of the thiazole ring system and is the group R5-N(R6)-C(O)—, and thegroup R3 is bonded in ring position 5 of the thiazole ring system, andrespective compounds are designated as compounds of the formula Im. Inanother embodiment of the invention, the group R2 is bonded in ringposition 4 of the thiazole ring system and is the group R5-N(R6)-CH₂—,and the group R3 is bonded in ring position 5 of the thiazole ringsystem, and respective compounds are designated as compounds of theformula In. In another embodiment of the invention, the group R2 isbonded in ring position 4 of the thiazole ring system and is the groupR7-C(O)—NH—CH₂—, and the group R3 is bonded in ring position 5 of thethiazole ring system, and respective compounds are designated ascompounds of the formula Io. In another embodiment of the invention, thegroup R2 is bonded in ring position 4 of the thiazole ring system and isthe group R7-S(O)₂—NH—CH₂—, and the group R3 is bonded in ring position5 of the thiazole ring system, and respective compounds are designatedas compounds of the formula Ip.

The groups Ar, R3, R4, R5, R6 and R7 in the compounds of the formulaeIg, Ih, Ij, Ik, Im, In, Io and Ip are defined as in the compounds of theformula I.

In one embodiment of the invention, the group R3 is selected from theseries consisting of hydrogen, halogen and (C₁-C₄)-alkyl, in anotherembodiment from the series consisting of hydrogen and halogen, inanother embodiment from the series consisting of hydrogen, fluorine andchlorine, in another embodiment from the series consisting of hydrogenand (C₁-C₄)-alkyl, and in another embodiment R3 is hydrogen. In oneembodiment of the invention, a (C₁-C₄)-alkyl group representing R3 orpresent in R3 is (C₁-C₂)-alkyl, in another embodiment it is methyl,wherein alkyl groups including methyl groups can also be substituted byone or more fluorine substituents and, for example, trifluoromethylgroups be present, as applies to alkyl groups in general.

As indicated above, in the free binding sites of the chroman ring, i.e.binding sites in positions 2, 3, 4, 5, 7 and 8 of the chroman ringsystem which are not occupied by bonds within the ring or the bond tothe group Ar, hydrogen atoms or substituents selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O— can be presentwhich represent groups R4. In one embodiment of the invention, in thefree binding site in position 2 of the chroman ring system, i.e. thefree binding site of the ring carbon atom which carries the group Ar, ahydrogen atom is present, and in the free binding sites in positions 3,4, 5, 7 and 8 of the chroman ring system hydrogen atoms or substituentsselected from the series consisting of halogen, (C₁-C₄)-alkyl and(C₁-C₄)-alkyl-O— are present. In another embodiment of the invention, inthe free binding sites in positions 2, 3 and 4 of the chroman ringsystem hydrogen atoms are present, and in the free binding sites inpositions 5, 7 and 8 of the chroman ring system hydrogen atoms orsubstituents selected from the series consisting of halogen,(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O— are present. In another embodiment ofthe invention, in the free binding sites in positions 2 and 5 of thechroman ring system hydrogen atoms are present, and in the free bindingsites in positions 3, 4, 7 and 8 of the chroman ring system hydrogenatoms or substituents selected from the series consisting of halogen,(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O— are present. In another embodiment ofthe invention, in the free binding sites in positions 2, 5, 7 and 8 ofthe chroman ring system hydrogen atoms are present, and in the freebinding sites in positions 3 and 4 of the chroman ring system hydrogenatoms or substituents selected from the series consisting of halogen,(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O— are present. In one embodiment, thenumber of groups R4 which are different from hydrogen, i.e. the numberof substituents R4 which are selected from halogen, (C₁-C₄)-alkyl and(C₁-C₄)-alkyl-O—, is 3, in another embodiment it is 2, in anotherembodiment it is 1, and in another embodiment it is 0, and in the latterembodiment thus no groups R4 which are different from hydrogen arepresent in the chroman ring system, and hydrogen atoms are present inall its free binding sites. In one embodiment. R4 is hydrogen or one ormore identical or different substituents selected from the seriesconsisting of halogen and (C₁-C₄)-alkyl, in another embodiment R4 ishydrogen or one or more identical or different substituents selectedfrom the series consisting of fluorine, chlorine and (C₁-C₄)-alkyl. Inone embodiment. R4 in the free binding sites in positions 2, 3 and 4 ofthe chroman ring system is hydrogen or one or more identical ordifferent substituents selected from the series consisting of fluorineand (C₁-C₄)-alkyl, in another embodiment R4 in the free binding sites inpositions 2, 3 and 4 of the chroman ring system is hydrogen or one ormore identical or different substituents selected from the seriesconsisting of (C₁-C₄)-alkyl, and R4 in the free binding sites inpositions 5, 7 and 8 of the chroman ring system is hydrogen or one ormore identical or different substituents selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in anotherembodiment R4 in the free binding sites in positions 5, 7 and 8 of thechroman ring system is hydrogen or one or more identical or differentsubstituents selected from the series consisting of halogen and(C₁-C₄)-alkyl, in another embodiment R4 in the free binding sites inpositions 5, 7 and 8 of the chroman ring system is hydrogen or one ormore identical or different substituents selected from the seriesconsisting of halogen. In one embodiment of the invention, a(C₁-C₄)-alkyl group representing R4 or present in R4 is (C₁-C₂)-alkyl,in another embodiment it is methyl.

In one embodiment of the invention, R5 and R6 are independently of oneanother selected from the series consisting of hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₆-C₁₀)-bicycloalkyl and Het2, in anotherembodiment from the series consisting of hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₆-C₁₀)-bicycloalkyl, in another embodiment fromthe series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl andHet2, in another embodiment from the series consisting of hydrogen,(C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, in another embodiment from theseries consisting of hydrogen and (C₁-C₆)-alkyl, wherein in all theseembodiment (C₁-C₆)-alkyl is unsubstituted or substituted by one or moreidentical or different substituents R10, and (C₃-C₇)-cycloalkyl,(C₆-C₁₀)-bicycloalkyl and Het2 all are unsubstituted or substituted byone or more identical or different substituents R11, or the groups R5and R6, together with the nitrogen atom carrying them, form a 4-memberedto 10-membered, monocyclic or bicyclic, saturated or partiallyunsaturated heterocycle which, in addition to the nitrogen atom carryingR5 and R6, comprises 0 or 1 further ring heteroatom selected from theseries consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents R12. In another embodiment of the invention. R5 and R6 areindependently of one another selected from the series consisting ofhydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₆-C₁₀)-bicycloalkyl andHet2, in another embodiment from the series consisting of hydrogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₆-C₁₀-bicycloalkyl, in anotherembodiment from the series consisting of hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and Het2, in another embodiment from the seriesconsisting of hydrogen, (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, in anotherembodiment from the series consisting of hydrogen and (C₁-C₆)-alkyl,wherein in all these embodiment (C₁-C₆)-alkyl is unsubstituted orsubstituted by one or more identical or different substituents R10, and(C₃-C₇)-cycloalkyl, (C₆-C₁₀)-bicycloalkyl and Het2 all are unsubstitutedor substituted by one or more identical or different substituents R11.

In one embodiment of the invention, one of the groups R5 and R6 isselected from the series consisting of hydrogen and (C₁-C₆)-alkyl, inanother embodiment from the series consisting of hydrogen and(C₁-C₄)-alkyl, in another embodiment from the series consisting ofhydrogen and methyl, and in another embodiment is hydrogen, and theother of the groups R5 and R6 is selected from the series consisting ofhydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₆-C₁₆)-bicycloalkyl andHet2, in another embodiment from the series consisting of hydrogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₆-C₁₀-bicycloalkyl, in anotherembodiment from the series consisting of hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and Het2, in another embodiment from the seriesconsisting of hydrogen, (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, in anotherembodiment from the series consisting of hydrogen and (C₁-C₆)-alkyl,wherein in all these embodiment (C₁-C₆)-alkyl, (C₁-C₄)-alkyl and methylrepresenting R5 or R6 is unsubstituted or substituted by one or moreidentical or different substituents R10, and (C₃-C₇)-cycloalkyl,(C₆-C₁₀)-bicycloalkyl and Het2 all are unsubstituted or substituted byone or more identical or different substituents R11, or the groups R5and R6, together with the nitrogen atom carrying them, form a 4-memberedto 10-membered, monocyclic or bicyclic, saturated or partiallyunsaturated heterocycle which, in addition to the nitrogen atom carryingR5 and R6, comprises 0 or 1 further ring heteroatom selected from theseries consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents R12. In another embodiment of the invention, one of thegroups R5 and R6 is selected from the series consisting of hydrogen and(C₁-C₆)-alkyl, in another embodiment from the series consisting ofhydrogen and (C₁-C₄)-alkyl, in another embodiment from the seriesconsisting of hydrogen and methyl, and in another embodiment ishydrogen, and the other of the groups R5 and R6 is selected from theseries consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,(C₆-C₁₀)-bicycloalkyl and Het2, in another embodiment from the seriesconsisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₆-C₁₀)-bicycloalkyl, in another embodiment from the series consistingof hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and Het2, in anotherembodiment from the series consisting of hydrogen, (C₁-C₆)-alkyl and(C₃-C₇)-cycloalkyl, in another embodiment from the series consisting ofhydrogen and (C₁-C₆)-alkyl, wherein in all these embodiment(C₁-C₆)-alkyl, (C₁-C₄)-alkyl and methyl representing R5 or R6 isunsubstituted or substituted by one or more identical or differentsubstituents R10, and (C₃-C₇)-cycloalkyl, (C₆-C₁₀)-bicycloalkyl and Het2all are unsubstituted or substituted by one or more identical ordifferent substituents R11.

In one embodiment of the invention, one of the groups R5 and R6 isselected from the series consisting of hydrogen and (C₁-C₆)-alkyl, inanother embodiment from the series consisting of hydrogen and(C₁-C₄)-alkyl, in another embodiment from the series consisting ofhydrogen and methyl, and in another embodiment is hydrogen, and theother of the groups R5 and R6 is selected from the series consisting of(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₆-C₁₀)-bicycloalkyl and Het2, inanother embodiment from the series consisting of (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₆-C₁₀)-bicycloalkyl, in another embodiment fromthe series consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and Het2, inanother embodiment from the series consisting of (C₁-C₆)-alkyl and(C₃-C₇)-cycloalkyl, in another embodiment from the series consisting of(C₁-C₆)-alkyl, wherein in all these embodiment (C₁-C₆)-alkyl,(C₁-C₄)-alkyl and methyl representing R5 or R6 is unsubstituted orsubstituted by one or more identical or different substituents R10, and(C₃-C₇)-cycloalkyl, (C₆-C₁₀)-bicycloalkyl and Het2 all are unsubstitutedor substituted by one or more identical or different substituents R11,or the groups R5 and R6, together with the nitrogen atom carrying them,form a 4-membered to 10-membered, monocyclic or bicyclic, saturated orpartially unsaturated heterocycle which, in addition to the nitrogenatom carrying R5 and R6, comprises 0 or 1 further ring heteroatomselected from the series consisting of nitrogen, oxygen and sulfur, andwhich is unsubstituted or substituted by one or more identical ordifferent substituents R12. In another embodiment of the invention, oneof the groups R5 and R6 is selected from the series consisting ofhydrogen and (C₁-C₆)-alkyl, in another embodiment from the seriesconsisting of hydrogen and (C₁-C₄)-alkyl, in another embodiment from theseries consisting of hydrogen and methyl, and in another embodiment ishydrogen, and the other of the groups R5 and R6 is selected from theseries consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,(C₆-C₁₀)-bicycloalkyl and Het2, in another embodiment from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₆-C₁₀)-bicycloalkyl, in another embodiment from the series consistingof (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and Het2, in another embodimentfrom the series consisting of (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, inanother embodiment from the series consisting of (C₁-C₆)-alkyl, whereinin all these embodiment (C₁-C₆)-alkyl, (C₁-C₄)-alkyl and methylrepresenting R5 or R6 is unsubstituted or substituted by one or moreidentical or different substituents R10, and (C₃-C₇)-cycloalkyl,(C₆-C₁₀)-bicycloalkyl and Het2 all are unsubstituted or substituted byone or more identical or different substituents R11.

In one embodiment of the invention, a (C₁-C₆)-alkyl group representingR5 or R6 is a (C₁-C₄)-alkyl group, in another embodiment a (C₁-C₃)-alkylgroup, in another embodiment a (C₁-C₂)-alkyl group, in anotherembodiment any one or more groups selected from the series consisting ofbutyl, propyl, isopropyl, ethyl and methyl, for example selected fromthe series consisting of methyl, ethyl and propyl, which are allunsubstituted or substituted by one or more, for example 1, 2 or 3, or 1or 2, or 1, identical or different substituents R10, which substituentscan be present in any positions, for example in position 1 and/or inposition 2 of an ethyl group representing R5 or R6, or in position 1and/or in position 2 and/or in position 3 of a propyl group representingR5 or R6.

In one embodiment of the invention, the number of identical or differentsubstituents R10 which are optionally present in a (C₁-C₆)-alkyl grouprepresenting R5 or R6, is 1, 2, 3 or 4, in another embodiment it is 1, 2or 3, in another embodiment it is 1 or 2, in another embodiment it is 1.In one embodiment, the number of groups R14 representing substituentsR10, which are optionally present in an (C₁-C₆)-alkyl group representingR5 or R6 besides any other substituents R10, is 1 or 2, in anotherembodiment it is 1, in another embodiment it is 0 (zero), i.e., in thelatter embodiment R10 is as defined, but is not R14. In one embodiment,the number of oxo groups representing substituents R10, which areoptionally present in an (C₁-C₆)-alkyl group representing R5 or R6besides any other substituents R10, is 1 or 2, in another embodiment itis 1. In one embodiment, the number of groups selected from the seriesconsisting of R16-N(R17)-C(O)—. R19-O—C(O)— andR16-N(R17)-S(O)₂-representing substituents R10, which are optionallypresent in an (C₁-C₆)-alkyl group representing R5 or R6 besides anyother substituents R10, is 1 or 2, in another embodiment it is 1.

In one embodiment of the invention, the number of identical or differentsubstituents R11 which are optionally present in (C₃-C₇)-cycloalkyl,(C₆-C₁₀)-bicycloalkyl and Het2 groups representing R5 or R6, isindependently of each other 1, 2, 3 or 4, in another embodiment it is 1,2 or 3, in another embodiment it is 1 or 2, in another embodiment itis 1. In one embodiment, the number of groups R14 representingsubstituents R11, which are optionally present in (C₃-C₇)-cycloalkyl,(C₆-C₁₀)-bicycloalkyl and Het2 groups representing R5 or R6 besides anyother substituents R11, is 1 or 2, in another embodiment it is 1, inanother embodiment it is 0. In one embodiment, the number of oxo groupsrepresenting substituents R11, which are optionally present in(C₃-C₇)-cycloalkyl, (C₆-C₁₀)-bicycloalkyl and Het2 groups representingR5 or R6 besides any other substituents R11, is 1 or 2, in anotherembodiment it is 1. In one embodiment, the number of groups selectedfrom the series consisting of R19-O—C(O)—(C₁-C₄)-alkyl-,R16-N(R17)-C(O)—, R19-O—C(O)— and R16-N(R17)-S(O)₂-representingsubstituents R11, which are optionally present in (C₃-C₇)-cycloalkyl,(C₆-C₁₀)-bicycloalkyl and Het2 groups representing R5 or R6 besides anyother substituents R11, is 1 or 2, in another embodiment it is 1.

The monocyclic or bicyclic heterocycle which can be formed by the groupsR5 and R6 together with the nitrogen atom carrying them, whichheterocycle is thus bonded via a ring nitrogen atom, can be 4-membered,5-membered, 6-membered, 7-membered, 8-membered, 9-membered or10-membered. In one embodiment of the invention, this heterocycle is5-membered to 10-membered, in another embodiment it is 5-membered to8-membered, in another embodiment it is 5-membered or 6-membered. In oneembodiment of the invention, a monocyclic heterocycle formed by thegroups R5 and R6 together with the nitrogen atom carrying them, is4-membered, 5-membered, 6-membered or 7-membered, and a bicyclicheterocycle formed by the groups R5 and R6 together with the nitrogenatom carrying them, is 6-membered, 7-membered, 8-membered, 9-membered or10-membered. In one embodiment, a heterocycle formed by the groups R5and R6 together with the nitrogen atom carrying them, is monocyclic, inanother embodiment it is bicyclic. The two cycles in a bicyclicheterocyclic group formed by the groups R5 and R6 together with thenitrogen atom carrying them, can be fused or form a bridged bicycle or aspirocycle. In one embodiment, a heterocycle formed by the groups R5 andR6 together with the nitrogen atom carrying them, is saturated orcontains one double bond within the ring, in another embodiment it issaturated. In one embodiment, the further ring heteroatom which isoptionally present in a heterocycle formed by the groups R5 and R6together with the nitrogen atom carrying them, is selected from theseries consisting of nitrogen and oxygen, in another embodiment it is anitrogen atom, and in another embodiment it is an oxygen atom. Examplesof heterocyclic groups, from any one or more of which the heterocyclicgroups formed by the groups R5 and R6 together with the nitrogen atomcarrying them is selected in one embodiment of the invention, are thegroups of the following formulae,

in which the line crossed with the symbol

represents the free bond via which the group is bonded. The bondoriginating at the substituent R12 which is depicted in these formulae,which is not directed to a specific atom, indicates that theseheterocyclic groups are optionally substituted by one or more identicalor different substituents R12 which can be present in any positions.

In one embodiment of the invention, the number of identical or differentsubstituents R12 which are optionally present in a heterocycle formed byR5 and R6 together with the nitrogen atom carrying them, is 1, 2, 3 or4, in another embodiment it is 1, 2 or 3, in another embodiment it is 1or 2, in another embodiment it is 1. In one embodiment, the number ofgroups R14 representing substituents R12, which are optionally presentin a heterocycle formed by R5 and R6 together with the nitrogen atomcarrying them besides any other substituents R12, is 1 or 2, in anotherembodiment it is 1, in another embodiment it is 0. In one embodiment,the number of oxo groups representing substituents R12, which areoptionally present in a heterocycle formed by R5 and R6 together withthe nitrogen atom carrying them besides any other substituents R12, is 1or 2, in another embodiment it is 1. In one embodiment, the number ofgroups selected from the series consisting of R19-O—C(O)—(C₁-C₄)-alkyl-,R16-N(R17)-C(O)—, R19-O—C(O)— and R16-N(R17)-S(O)₂— representingsubstituents R12, which are optionally present in a heterocycle formedby R5 and R6 together with the nitrogen atom carrying them besides anyother substituents R12, is 1 or 2, in another embodiment it is 1.

In one embodiment of the invention, R7 is in any of its occurrences,independently of other occurrences, selected from the series consistingof (C₁-C₆)-alkyl, phenyl, Het2 and Het3, in another embodiment from theseries consisting of (C₁-C₆)-alkyl, Het2 and Het3, in another embodimentfrom the series consisting of (C₁-C₆)-alkyl and Het2, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl and Het3, inanother embodiment from the series consisting of phenyl and Het3, and inanother embodiment is (C₁-C₆)-alkyl, and in another embodiment isphenyl, and in another embodiment is Het2, and in another embodiment isHet3, wherein all groups (C₁-C₆)-alkyl and Het2 are unsubstituted orsubstituted by one or more identical or different substituents R10, andall groups phenyl and Het3 are unsubstituted or substituted by one ormore identical or different substituents R13.

In one embodiment of the invention, the number of identical or differentsubstituents R10 which are optionally present in (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and Het2 groups representing R7, is independently ofeach other 1, 2 or 3, in another embodiment it is 1 or 2, in anotherembodiment it is 1. In one embodiment, the number of groups R14representing substituents R10, which are optionally present in(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and Het2 groups representing R7besides any other substituents R10, is 1 or 2, in another embodiment itis 1, in another embodiment it is 0. In one embodiment, the number ofoxo groups representing substituents R10, which are optionally presentin (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and Het2 groups representing R7besides any other substituents R10, is 1 or 2, in another embodiment itis 1. In one embodiment, the number of groups selected from the seriesconsisting of R16-N(R17)-C(O)—, R19-O—C(O)— and R16-N(R17)-S(O)₂—representing substituents R10, which are optionally present in(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and Het2 groups representing R7besides any other substituents R10, is 1 or 2, in another embodiment itis 1. In one embodiment of the invention, the number of identical ordifferent substituents R13 which are optionally present in phenyl andHet3 groups representing R7, is independently of each other 1, 2 or 3,in another embodiment it is 1 or 2, in another embodiment it is 1, inanother embodiment it is 0.

In one embodiment of the invention, R10 is selected from the seriesconsisting of R14, fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—,R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—,R16-N(R17)-, R18-C(O)—N(R17)-, R16-N(R17)-C(O)— and R19-O—C(O)—, inanother embodiment from the series consisting of fluorine, HO—, oxo,(C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, (C₁-C₆)-alkyl-S(O)_(n)—,R16-N(R17)-, R18-C(O)—N(R17)-, R16-N(R17)-C(O)—, R19-O—C(O)— andR16-N(R17)-S(O)₂—, in another embodiment from the series consisting ofR14, fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—,HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)- andR18-C(O)—N(R17)-, in another embodiment from the series consisting ofR14, fluorine, HO—, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—,HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)-,R18-C(O)—N(R17)-, R16-N(R17)-C(O)— and R19-O—C(O)—, in anotherembodiment from the series consisting of fluorine, HO—,(C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)-, R18-C(O)—N(R17)-,R16-N(R17)-C(O)— and R19-O—C(O)—, in another embodiment from the seriesconsisting of R14, fluorine, HO—, (C₁-C₆)-alkyl-O—, R15-C(O)—O—,R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)-,R18-C(O)—N(R17)-, R16-N(R17)-C(O)— and R19-O—C(O)—, in anotherembodiment from the series consisting of fluorine, HO—,(C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, R16-N(R17)-, R18-C(O)—N(R17)-, R16-N(R17)-C(O)— andR19-O—C(O)—, in another embodiment from the series consisting of R14,fluorine, HO—, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—,HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)- andR18-C(O)—N(R17)-, in another embodiment from the series consisting offluorine, HO—, (C₁-C₆)-alkyl-O—, R15-O(O)—O—, R15-NH—C(O)—O—,HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)- andR18-C(O)—N(R17)-, in another embodiment from the series consisting ofR14, HO—, (C₁-C₆)-alkyl-O—, R15-O(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)- andR18-C(O)—N(R17)-, in another embodiment from the series consisting ofHO—, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)- andR18-C(O)—N(R17)-, in another embodiment from the series consisting ofR14, HO—, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,(HO)₂P(O)—O— and (HO)₂P(O)—O—CH₂—O—C(O)—O—, in another embodiment fromthe series consisting of HO—, (C₁-C₆)-alkyl-O—, R15-C(O)—O—,R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O— and (HO)₂P(O)—O—CH₂—O—C(O)—O—,in another embodiment from the series consisting of R14, HO—,(C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O— and(HO)₂P(O)—O—, in another embodiment from the series consisting of HO—,(C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O— and(HO)₂P(O)—O—, in another embodiment from the series consisting of HO—,R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O— and (HO)₂P(O)—O—, in anotherembodiment from the series consisting of HO—, HO—S(O)₂—O— and(HO)₂P(O)—O—, in another embodiment from the series consisting of HO—and (HO)₂P(O)—O—, in another embodiment from the series consisting ofR14, HO— and (HO)₂P(O)—O—, in another embodiment from the seriesconsisting of R14 and HO—, and in another embodiment R10 is HO—, and inanother embodiment R10 is R14, wherein in case that more than onesubstituent R10 is present, the substituents R10 are independently ofone another defined as in any of these embodiments.

In one embodiment of the invention, R11 and R12 are independently of oneanother selected from the series consisting of (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, R16-N(R17)-R19-O—C(O)—(C₁-C₄)-alkyl-, R14, fluorine,HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)-, R18-C(O)—N(R17)-,R16-N(R17)-C(O)— and R19-O—C(O)—, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,R16-N(R17)-(C₁-C₄)-alkyl-, R19-O—C(O)—(C₁-C₄)-alkyl-, R14, fluorine,HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)-, R18-C(O)—N(R17)-and R19-O—C(O)—, in another embodiment from the series consisting of(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-,R19-O—C(O)—(C₁-C₄)-alkyl-, fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—,R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—,(HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)-, R18-C(O)—N(R17)- andR19-O—C(O)—, in another embodiment from the series consisting of(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-, fluorine,HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)- andR18-C(O)—N(R17)-, in another embodiment from the series consisting of(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-,R19-O—C(O)—(C₁-C₄)-alkyl-, fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—,R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)-,R18-C(O)—N(R17)- and R19-O—C(O)—, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,R16-N(R17)-(C₁-C₄)-alkyl-, fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—,R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)- andR18-C(O)—N(R17)-, in another embodiment from the series consisting of(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-, fluorine,HO—, oxo, (C₁-C₆)-alkyl-O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)- andR18-C(O)—N(R17)-, in another embodiment from the series consisting of(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-, fluorine,HO—, (C₁-C₆)-alkyl-O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)- andR18-C(O)—N(R17)-, in another embodiment from the series consisting of(C₁-C₄)-alkyl, HO—R16-N(R17)-(C₁-C₄)-alkyl-, fluorine, HO—, oxo,(C₁-C₆)-alkyl-O— and R16-N(R17)-, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,R16-N(R17)-(C₁-C₄)-alkyl-, fluorine, HO—, (C₁-C₆)-alkyl-O— andR16-N(R17)-, in another embodiment from the series consisting of(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-, fluorine,HO—, oxo and R16-N(R17)-, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, fluorine and oxo, in another embodimentfrom the series consisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,R16-N(R17)-(C₁-C₄)-alkyl-, fluorine, HO— and R16-N(R17)-, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-, HO— and R16-N(R17)-, inanother embodiment from the series consisting of (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-, R19-O—C(O)—(C₁-C₄)-alkyl-,HO—, R16-N(R17)- and R19-O—C(O)—, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,R16-N(R17)-(C₁-C₄)-alkyl-, HO—, R16-N(R17)- and R19-O—C(O)—, wherein incase that more than one substituent R11 or R12 is present, thesubstituents R11 and R12 are independently of one another defined as inany of these embodiments. In one embodiment, substituents R11 and R12which are bonded to a ring nitrogen atom, as can occur in the case ofthe group Het2 or the ring which can be formed by R5 and R6 togetherwith the nitrogen atom carrying them, are selected from the seriesconsisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,R16-N(R17)-(C₁-C₄)-alkyl- and R14, wherein R14 is bonded via a ringcarbon atom, in another embodiment from the series consisting of(C₁-C₄)-alkyl.

The explanations given above with respect to the ring which can beformed by two substituents R1 bonded to adjacent ring carbon atoms in Artogether with the carbon atoms carrying them, apply correspondingly tothe ring which can be formed by two substituents R13 bonded to adjacentring carbon atoms in R7. I.e., the ring which can be formed by twosubstituents R13 bonded to adjacent ring carbon atoms in R7, ismono-unsaturated because it is fused to an aromatic ring, i.e. a phenylgroup or a group Het3 representing R7, and two such groups R13 forming aring together with the carbon atoms carrying them can in other terms beregarded as together forming a divalent residue comprising a chain of 3to 5 atoms of which 0, 1 or 2 are identical or different heteroatomsselected from the series consisting of nitrogen, oxygen and sulfur. Theexamples of such divalent residues given above with respect to the ringwhich can be formed by two groups R1 together with the ring carbon atomscarrying them, apply likewise to the ring which can be formed by twosubstituents R13 together with the ring carbon atoms carrying them. Inone embodiment of the invention, the ring which can be formed by twogroups R13 bonded to adjacent ring carbon atoms in R7 together with thecarbon atoms carrying them, is a 5-membered or 6-membered, in anotherembodiment a 5-membered, in another embodiment a 6-membered ring. In oneembodiment of the invention, the number of substituents selected fromthe series consisting of fluorine and (C₁-C₄)-alkyl, which can bepresent in a ring formed by two groups R13 bonded to adjacent ringcarbon atoms in R7 together with the carbon atoms carrying them, is 1, 2or 3, in another embodiment 1 or 2, in another embodiment 1. In oneembodiment of the invention, substituents which can be present in a ringformed by two groups R13 bonded to adjacent ring carbon atoms in R7together with the carbon atoms carrying them, are fluorine substituents,and in another embodiment they are (C₁-C₄)-alkyl substituents, forexample methyl substituents, and in another embodiment are substituentsin such a ring bonded to a ring nitrogen atom selected from the seriesconsisting of (C₁-C₄)-alkyl. In one embodiment, a ring formed by twosubstituents R13 bonded to adjacent ring carbon atoms in R7 togetherwith the carbon atoms carrying them, comprises 1 or 2, in anotherembodiment 2, identical or different ring heteroatoms, wherein in oneembodiment the ring heteroatoms are selected from the series consistingof nitrogen and sulfur, and in another embodiment 1 ring nitrogen and 1ring sulfur atom is present in such a ring.

In one embodiment of the invention, R13 is selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and R16-N(R17)-,in another embodiment from the series consisting of halogen,(C₁-C₄)-alkyl, HO— and (C₁-C₄)-alkyl-O—, in another embodiment from theseries consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, inanother embodiment from the series consisting of halogen, (C₁-C₄)-alkyland R16-N(R17)-, in another embodiment from the series consisting ofhalogen and (C₁-C₄)-alkyl, and two substituents R13 bonded to adjacentring carbon atoms in R7, together with the carbon atoms carrying them,can form a 5-membered to 7-membered mono-unsaturated ring whichcomprises 0, 1 or 2 identical or different ring heteroatoms selectedfrom the series consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of fluorine and(C₁-C₄)-alkyl. In another embodiment, R13 is selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, HO—, (C₁-C₄)-alkyl-O— andR16-N(R17)-, in another embodiment from the series consisting ofhalogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and R16-N(R17)-, in anotherembodiment from the series consisting of halogen, (C₁-C₄)-alkyl, HO— and(C₁-C₄)-alkyl-O—, in another embodiment from the series consisting ofhalogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodiment fromthe series consisting of halogen, (C₁-C₄)-alkyl and R16-N(R17)-, inanother embodiment from the series consisting of halogen and(C₁-C₄)-alkyl.

The monocyclic or bicyclic group R14 can be 3-membered, 4-membered,5-membered, 6-membered, 7-membered, 8-membered, 9-membered or10-membered.

In one embodiment of the invention, a monocyclic group R14 is3-membered, 4-membered, 5-membered, 6-membered or 7-membered, and abicyclic group R14 is 6-membered, 7-membered, 8-membered, 9-membered or10-membered. In one embodiment of the invention. R14 is monocyclic, inanother embodiment it is bicyclic. The two cycles in a bicyclic groupR14 can be fused or form a bridged bicycle or a spirocycle. Themonocyclic or bicyclic ring R14 can be saturated, i.e. not contain anydouble bonds within the ring system, or be partially unsaturated, i.e.contain one or more double bonds within the ring system, for example,one two, three or four double bonds, or one, two or three double bonds,or one or two double bonds, or one double bond, but is not fullyaromatic, i.e. it does not contain a cyclic system of six delocalized pielectrons in the case of a monocycle or of ten delocalized pi electronsin the case of a bicycle, or it can be aromatic. The number of doublebonds which can be present in ring, depends on the type of the ringsystem and the ring size. Partially unsaturated rings R14 include alsobicyclic ring systems in which one of the two cycles is aromatic and theother is not aromatic. The ring R14 can be carbocyclic, i.e. contain 0(zero) ring heteroatoms, or heterocyclic, i.e. contain 1, 2, 3 or 4identical or different ring heteroatoms. In one embodiment, the numberof ring heteroatoms which are present in R14 is 0, 1, 2 or 3, in anotherembodiment 0, 1 or 2, in another embodiment 0 or 1. In one embodiment ofthe invention, R14 is in any of its occurrences, independently of itsother occurrences, a carbocyclic ring, and in another embodiment it is aheterocyclic ring. In a bicyclic ring R14, ring heteroatoms can bepresent in one of the two rings or in both rings in any suitablepositions. In bridged and fused bicyclic rings, ring nitrogen atoms canalso be present in bridgehead positions and fusion positions. In oneembodiment of the invention, a 3-membered ring R14 is carbocyclic ring,in particular a cyclopropane ring, i.e., in this case the group R14 is acyclopropyl group. In one embodiment, ring heteroatoms which are presentin R14, are selected from the series consisting of nitrogen and oxygen,in another embodiment from the series consisting of nitrogen and sulfur,and in another embodiment they are nitrogen atoms. In anotherembodiment, R14 is as defined, but is not a pyrazolyl group which isunsubstituted or substituted by one or more identical or different(C₁-C₄)-alkyl substituents. R14 can be bonded via any ring carbon atomand any ring nitrogen atom which has a free binding position. In abicyclic group R14, the ring atom via which R14 is bonded, can bepresent in a saturated ring, a partially unsaturated ring or in anaromatic ring. In one embodiment of the invention, R14 is bonded in anyof its occurrences, independently of its other occurrences, via a ringcarbon atom, in another embodiment via a ring nitrogen atom.

Types of cyclic groups which are comprised by the definition of R14, arecycloalkyl groups, bicycloalkyl groups, phenyl groups, naphthyl groupsincluding naphthalen-1-yl groups and naphthalen-2-yl groups, partiallyhydrogenated naphthyl groups such as 1,2,3,4-tetrahydronaphthalenylgroups, monocyclic and bicyclic aromatic heterocyclic groups such as thegroups Het1 and Het3, and saturated and partially unsaturated monocyclicand bicyclic heterocyclic groups such as the group Het2. Theexplanations given above and below with respect to such groups applycorrespondingly to such groups representing R14, as do the explanationsgiven above with respect to heterocyclic groups in general. Examples ofgroups, from any one or more of which the group R14 is selected in oneembodiment of the invention, are the groups of the following formulae,

in which the line crossed with the symbol

represents the free bond via which the group is bonded. The bondoriginating at the substituent R20 which is depicted in these formulae,which is not directed to a specific atom, indicates that these groupsare optionally substituted by one or more identical or differentsubstituents R20, which can be present in any positions.

In one embodiment of the invention, the number of identical or differentsubstituents R20 which are optionally present in the group R14, is 1, 2,3 or 4, in another embodiment it is 1, 2 or 3, in another embodiment itis 1 or 2, in another embodiment it is 1. In one embodiment, the numberof oxo groups representing substituents R20, which are optionallypresent in R14 besides any other substituents R20, is 1 or 2, in anotherembodiment it is 1. In one embodiment, the number of groups selectedfrom the series consisting of R16-N(R17)-C(O)—. R19-O—C(O)— andR16-N(R17)-S(O)₂-representing substituents R20, which are optionallypresent in R14 besides any other substituents R20, is 1 or 2, in anotherembodiment it is 1.

In one embodiment of the invention, R15 is in any of its occurrences,independently of its other occurrences, selected from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, in another embodiment from the seriesconsisting of (C₁-C₆)-alkyl, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, and in another embodiment R15 is methyl.

In one embodiment of the invention, R16 and R17 are in any of theiroccurrences, independently of other occurrences, and independently ofone another, selected from the series consisting of hydrogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,in another embodiment from the series consisting of hydrogen and(C₁-C₆)-alkyl, in another embodiment from the series consisting ofhydrogen and (C₁-C₄)-alkyl, in another embodiment from the seriesconsisting of hydrogen and methyl, or the groups R16 and R17, togetherwith the nitrogen atom carrying them, form a 4-membered to 7-membered,monocyclic saturated heterocycle which, in addition to the nitrogen atomcarrying R16 and R17, comprises 0 or 1 further ring heteroatom selectedfrom the series consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of fluorine and(C₁-C₄)-alkyl. In another embodiment. R16 and R17 are in any of theiroccurrences, independently of other occurrences, and independently ofone another, selected from the series consisting of hydrogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloakyl-(C₁-C₄)-alkyl-,in another embodiment from the series consisting of hydrogen and(C₁-C₆)-alkyl, in another embodiment from the series consisting ofhydrogen and (C₁-C₄)-alkyl, in another embodiment from the seriesconsisting of hydrogen and methyl.

The monocyclic heterocycle which can be formed by the groups R16 and R17together with the nitrogen atom carrying them, which heterocycle is thusbonded via a ring nitrogen atom, can be 4-membered, 5-membered,6-membered or 7-membered. In one embodiment of the invention, theheterocycle formed by the groups R16 and R17 together with the nitrogenatom carrying them, is 5-membered or 6-membered, in another embodimentit is 6-membered. In one embodiment, the further ring heteroatom whichis optionally present in a heterocycle formed by the groups R16 and R17together with the nitrogen atom carrying them, is selected from theseries consisting of nitrogen and oxygen, in another embodiment it is anitrogen atom, and in another embodiment it is an oxygen atom. In oneembodiment of the invention, the number of substituents selected fromthe series consisting of fluorine and (C₁-C₄)-alkyl, which can bepresent in a ring formed by the groups R16 and R17 together with thenitrogen atom carrying them, is 1, 2 or 3, in another embodiment 1 or 2,in another embodiment 1. In one embodiment of the invention,substituents which can be present in a ring formed by the groups R16 andR17 together with the nitrogen atom carrying them, are fluorinesubstituents, and in another embodiment they are (C₁-C₄)-alkylsubstituents, for example methyl substituents, and in another embodimentare substituents in such a ring bonded to a ring nitrogen atom selectedfrom the series consisting of (C₁-C₄)-alkyl. Examples of heterocyclicgroups, from any one or more of which the heterocyclic groups formed bythe groups R16 and R17 together with the nitrogen atom carrying them isselected in one embodiment of the invention, are azetidin-1-yl,pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, and4-methylpiperazin-1-yl.

In one embodiment of the invention, R18 is in any of its occurrences,independently of its other occurrences, selected from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, in another embodiment from the seriesconsisting of (C₁-C₆)-alkyl, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, and in another embodiment R18 is methyl.

In one embodiment of the invention, R19 is in any of its occurrences,independently of its other occurrences, selected from the seriesconsisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, in another embodiment from the seriesconsisting of hydrogen and (C₁-C₆)-alkyl, in another embodiment from theseries consisting of hydrogen and (C₁-C₄)-alkyl, in another embodimentfrom the series consisting of (C₁-C₄)-alkyl, and in another embodimentR19 is hydrogen.

In one embodiment of the invention, R20 is selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₃-C₇)-cycloalkyl, HO—, oxo,(C₁-C₆)-alkyl-O—, R15-C(O)—O—,R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—,R16-N(R17)-, R18-C(O)—N(R17)-, R18-O—C(O)—N(R17)-, NC—, R18-C(O)—,R16-N(R17)-C(O)— and R19-O—C(O)—, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₃-C₇)-cycloalkyl, HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—,R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—,R16-N(R17)-, R18-C(O)—N(R17)-, R18-O—C(O)—N(R17)- and NC—, in anotherembodiment from the series consisting of halogen, (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, (C₃-C₇)-cycloalkyl, HO—, oxo, (C₁-C₆)-alkyl-O—,R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)- andNC—, in another embodiment from the series consisting of halogen,(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₃-C₇)-cycloalkyl, HO—, oxo,(C₁-C₆)-alkyl-O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)- and NC—, inanother embodiment from the series consisting of halogen, (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, (C₃-C₇)-cycloalkyl, HO—, oxo, (C₁-C₆)-alkyl-O—,(HO)₂P(O)—O—, R16-N(R17)- and NC—, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₃-C₇)-cycloalkyl, HO—, oxo, R16-N(R17)- and NC—, in another embodimentfrom the series consisting of halogen, (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, HO—, oxo, R16-N(R17)- and NC—, in another embodimentfrom the series consisting of halogen, (C₁-C₄)-alkyl, oxo,(C₁-C₆)-alkyl-O— and R16-N(R17)-, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl, (C₁-C₆)-alkyl-O— and R16-N(R17)-,in another embodiment from the series consisting of (C₁-C₄)-alkyl andoxo, wherein in case that more than one substituent R20 is present, thesubstituents R20 are independently of one another defined as in any ofthese embodiments.

In one embodiment of the invention, the aromatic group Het1 is in any ofits occurrences, independently of other occurrences, a 5-memberedheterocycle which comprises one ring heteroatom which is selected fromthe series consisting of nitrogen, oxygen and sulfur, and a further ringheteroatom which is a ring nitrogen atom, or it is 6-memberedheterocycle which comprises one or two ring nitrogen atoms, in anotherembodiment Het1 is selected from the series consisting of the aromaticheterocycles pyrazole, imidazole, isoxazole, oxazole, thiazole,pyridine, pyrimidine and pyrazine, in another embodiment from the seriesconsisting of pyrazole, isoxazole, oxazole, thiazole, pyridine andpyrimidine, in another embodiment from the series consisting ofpyrazole, isoxazole, oxazole, thiazole and pyridine, which are allunsubstituted or substituted as indicated. In one embodiment, the groupHet1 is bonded via a ring carbon atom. In one embodiment, the number ofsubstituents which are optionally present in a group Het1, is 1, 2 or 3,in another embodiment 1 or 2, in another embodiment 1. In oneembodiment, the substituents which are optionally present in Het1 areselected from the series consisting of halogen and (C₁-C₄)-alkyl. In oneembodiment, a substituent which is bonded to a ring nitrogen atom, suchas in a pyrrole, pyrazole or imidazole ring, is selected from the seriesconsisting of (C₁-C₄)-alkyl.

The heterocyclic group Het2 can be 4-membered, 5-membered, 6-membered,7-membered, 8-membered, 9-membered or 10-membered. In one embodiment ofthe invention, a monocyclic group Het2 is 4-membered, 5-membered,6-membered or 7-membered, and a bicyclic group Het2 is 6-membered,7-membered, 8-membered, 9-membered or 10-membered. In one embodiment ofthe invention, Het2 is in any of its occurrences, independently of otheroccurrences, monocyclic, and in another embodiment it is bicyclic. Thetwo cycles in a bicyclic group Het2, can be fused or form a bridgedbicycle or a spirocycle. In one embodiment, the group Het2 is saturatedor contains one double bond within the ring, in another embodiment it issaturated. In one embodiment, the further ring heteroatom which isoptionally present in a group Het2, is selected from the seriesconsisting of nitrogen and oxygen, in another embodiment it is anitrogen atom, and in another embodiment it is an oxygen atom. Het2 canbe bonded via any ring carbon atom and any ring nitrogen atom which hasa free binding position. In one embodiment of the invention. Het2 isbonded in any of its occurrences, independently of its otheroccurrences, via a ring carbon atom, in another embodiment via a ringnitrogen atom. Examples of heterocyclic groups, from any one or more ofwhich Het2 is selected in one embodiment of the invention, areazetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl,thiomorpholinyl, piperazinyl and 3-azabicyclo[3.1.0]hexane, which in oneembodiment are bonded via ring carbon atom and, for example, are theresidues azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl and3-azabicyclo[3.1.0]hexan-6-yl.

In one embodiment of the invention, the aromatic group Het3 is a5-membered or 6-membered monocyclic heterocycle or an 8-membered,9-membered or 10-membered bicyclic heterocycle, in another embodiment a5-membered or 6-membered monocyclic heterocycle or a 9-membered or10-membered bicyclic heterocycle. In a bicyclic heterocycle representingHet3, the ring heteroatoms can be present in one of the rings or both ofthe rings. In one embodiment, one of the ring heteroatoms in Het3 is aring nitrogen atom and no further ring heteroatom is present, or asecond ring heteroatom is present which is selected from the seriesconsisting of nitrogen, oxygen and sulfur. In one embodiment, Het3 isselected from the series consisting of the aromatic heterocyclespyrazole, imidazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine,pyrazine, benzimidazole, benzoxazole, benzthiazole, quinoline andisoquinoline, in another embodiment from the series consisting ofpyrazole, imidazole, isoxazole, oxazole, thiazole, pyridine,benzimidazole, benzoxazole and benzthiazole, in another embodiment fromthe series consisting of pyrazole, imidazole, isoxazole, thiazole,pyridine, benzimidazole and benzthiazole, in another embodiment from theseries consisting of pyrazole, imidazole, isoxazole, thiazole, pyridineand benzthiazole.

In one embodiment of the invention, the substituents in a phenyl groupin any occurrence in a compound of the formula I, independently of anyother occurrences, are selected from the series consisting of halogenand (C₁-C₄)-alkyl, unless specified otherwise. In one embodiment, thenumber of substituents in a phenyl group is 1, 2 or 3, in anotherembodiment 1 or 2, in another embodiment 1, unless specified otherwise.

In one embodiment of the invention, the chiral carbon atom in position 2of the chroman ring system in a compound of the formula I is present, oris essentially present, for example with a molar ratio of the twostereoisomers of 98:2, or 99:1, or greater, in uniform configuration,either in R configuration or in S configuration, as is indicated by thewavy wedge in the compound of the formula Ig. In another embodiment ofthe invention, the chiral carbon atom in position 2 of the chroman ringsystem in a compound of the formula I is present, or is essentiallypresent, for example with a molar ratio of the two stereoisomers of98:2, or 99:1, or greater, in the configuration depicted in formula Ir,i.e. in the respective compound of the formula I the group Ar is locatedabove the plane which may be assumed to be formed by the chroman ringsystem arranged as depicted in formulae Ir and Is, which configurationis R configuration in case all groups R4 are hydrogen. In anotherembodiment of the invention, the chiral carbon atom in position 2 of thechroman ring system in a compound of the formula I is present, or isessentially present, for example with a molar ratio of the twostereoisomers of 98:2, or 99:1, or greater, in the configurationdepicted in formula Is, i.e. in the respective compound of the formula Ithe group Ar is located below the plane which may be assumed to beformed by the chroman ring system arranged as depicted in formulae Irand Is, which configuration is S configuration in case all groups R4 arehydrogen.

The groups Ar, R2, R3 and R4 in the compounds of the formulae Iq, Ir andIs are defined as in the compounds of the formula I.

A subject of the invention are all compounds of the formula I whereinany one or more structural elements such as groups, residues,substituents and numbers are defined as in any of the specifiedembodiments or definitions of the elements, or have one or more of thespecific meanings which are mentioned herein as examples of elements,wherein all combinations of one or more definitions of compounds orelements and/or specified embodiments and/or specific meanings ofelements are a subject of the present invention. Also with respect toall such compounds of the formula I, all their stereoisomeric forms andmixtures of stereoisomeric forms in any ratio, and theirpharmaceutically acceptable salts are a subject of the presentinvention.

As an example of compounds of the invention which with respect to anystructural elements are defined as in specified embodiments of theinvention or definitions of such elements, compounds of the formula Imay be mentioned wherein

-   Ar is selected from the series consisting of phenyl, thiophenyl,    pyridinyl and pyrazinyl, which are all unsubstituted or substituted    by one or more identical or different substituents R1;-   R1 is selected from the series consisting of halogen, (C₁-C₆)-alkyl,    (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, HO—,    (C₁-C₆)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O— and (C₁-C₆)-alkyl-S(O)_(n)—;-   R2 is selected from the series consisting of R5-N(R6)-C(O)—,    R5-N(R6)-CH₂—, R7-C(O)—NH—CH₂— and R7-S(O)₂—NH—CH₂—;-   R3 is selected from the series consisting of hydrogen, halogen and    (C₁-C₄)-alkyl;-   R4 is hydrogen or one or more identical or different substituents    selected from the series consisting of halogen and (C₁-C₄)-alkyl;-   R5 and R6 are independently of one another selected from the series    consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,    (C₆-C₁₀)-bicycloalkyl and Het2, wherein (C₁-C₆)-alkyl is    unsubstituted or substituted by one or more identical or different    substituents R10, and (C₃-C₇)-cycloalkyl, (C₆-C₁₀)-bicycloalkyl and    Het2 all are unsubstituted or substituted by one or more identical    or different substituents R11,    or the groups R5 and R6, together with the nitrogen atom carrying    them, form a 4-membered to 10-membered, monocyclic or bicyclic,    saturated heterocycle which, in addition to the nitrogen atom    carrying R5 and R6, comprises 0 or 1 further ring heteroatom    selected from the series consisting of nitrogen, oxygen and sulfur,    and which is unsubstituted or substituted by one or more identical    or different substituents R12;-   R7 is selected from the series consisting of (C₁-C₆)-alkyl, Het2 and    Het3, wherein (C₁-C₆)-alkyl and Het2 all are unsubstituted or    substituted by one or more identical or different substituents R10,    and Het3 is unsubstituted or substituted by one or more identical or    different substituents R13;-   R10 is selected from the series consisting of R14, fluorine, HO—,    oxo,(C₁-C₆)-alkyl-O—R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,    (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)-,    R18-C(O)—N(R17)-, R16-N(R17)-C(O)— and R19-O—C(O)—;-   R11 and R12 are independently of one another selected from the    series consisting of (C₁-C₄)-alkyl, R18-N(R17)-(C₁-C₄)-alkyl-,    R19-O—C(O)—(C₁-C₄)-alkyl-, fluorine, HO—, oxo, ,(C₁-C₆)-alkyl-O—,    R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—,    (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)-, R18-C(O)—N(R17)-,    R16-N(R17)-C(O)— and R19-O—C(O)—;-   R13 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and R16-N(R17)-;-   R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring    which is saturated, partially unsaturated or aromatic and comprises    0, 1, 2 or 3 identical or different ring heteroatoms selected from    the series consisting of nitrogen, oxygen and sulfur, and which is    unsubstituted or substituted by one or more identical or different    substituents R20;-   R15 and R18 are independently of one another selected from the    series consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-;-   R16 and R17 are independently of one another selected from the    series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,    or the groups R16 and R17, together with the nitrogen atom carrying    them, form a 5-membered to 6-membered, monocyclic saturated    heterocycle which, in addition to the nitrogen atom carrying R16 and    R17, comprises 0 or 1 further ring heteroatom selected from the    series consisting of nitrogen, oxygen and sulfur, and which is    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;-   R19 is selected from the series consisting of hydrogen,    (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-;-   R20 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₃-C₇)-cycloalkyl, HO—, oxo,    (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,    (HO)₂P(O)—O—, R16-N(R17)- and NC—;-   Het2 is a 4-membered to 10-membered monocyclic or bicyclic,    saturated or partially unsaturated heterocycle comprising 1 or 2    identical or different ring heteroatoms selected from the series    consisting of nitrogen, oxygen and sulfur;-   Het3 is a 5-membered to 10-membered monocyclic or bicyclic aromatic    heterocycle comprising 1 or 2 identical or different ring    heteroatoms selected from the series consisting of nitrogen, oxygen    and sulfur;-   n is selected from the series consisting of 0, 1 and 2, wherein all    numbers n are independent of one another;-   wherein all cycloalkyl and bicycloalkyl groups, independently of any    other substituents which can be present on a cycloalkyl or    bicycloalkyl group, can be substituted by one or more identical    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents;-   in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and the pharmaceutically acceptable salt    thereof.

As another such example, compounds of the formula I may be mentioned,wherein

-   Ar is selected from the series consisting of phenyl, thiophenyl,    pyridinyl and pyrazinyl, which are all unsubstituted or substituted    by one or more identical or different substituents R1;-   R1 is selected from the series consisting of halogen, (C₁-C₆)-alkyl,    HO— and (C₁-C₆)-alkyl-O—;-   R2 is selected from the series consisting of R5-N(R6)-C(O)—,    R5-N(R6)-CH₂—, R7-C(O)—NH—CH₂— and R7-S(O)₂—NH—CH₂—;-   R3 is selected from the series consisting of hydrogen, halogen and    (C₁-C₄)-alkyl;-   R4 is hydrogen or one or more identical or different substituents    selected from the series consisting of halogen and (C₁-C₄)-alkyl;-   R5 and R6 are independently of one another selected from the series    consisting of hydrogen, (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl,    wherein (C₁-C₆)-alkyl is unsubstituted or substituted by one or more    identical or different substituents R10, and (C₃-C₇)-cycloalkyl is    unsubstituted or substituted by one or more identical or different    substituents R11,-   or the groups R5 and R6, together with the nitrogen atom carrying    them, form a 4-membered to 10-membered, monocyclic or bicyclic,    saturated heterocycle which, in addition to the nitrogen atom    carrying R5 and R6, comprises 0 or 1 further ring heteroatom    selected from the series consisting of nitrogen and oxygen, and    which is unsubstituted or substituted by one or more identical or    different substituents R12;-   R7 is selected from the series consisting of (C₁-C₆)-alkyl and Het3,    wherein (C₁-C₆)-alkyl is unsubstituted or substituted by one or more    identical or different substituents R10, and Het3 is unsubstituted    or substituted by one or more identical or different substituents    R13;-   R10 is selected from the series consisting of R14, fluorine, HO—,    oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,    (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)-,    R18-C(O)—N(R17)-, R16-N(R17)-C(O)— and R19-O—C(O)—;-   R11 and R12 are independently of one another selected from the    series consisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,    R16-N(R17)-(C₁-C₄)-alkyl-, fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—,    HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)- and R18-C(O)—N(R17)-;-   R13 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and R16-N(R17)-;-   R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring    which is saturated, partially unsaturated or aromatic and comprises    0, 1, 2 or 3 identical or different ring heteroatoms selected from    the series consisting of nitrogen, oxygen and sulfur, and which is    unsubstituted or substituted by one or more identical or different    substituents R20;-   R15 and R18 are independently of one another selected from the    series consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-;-   R16 and R17 are independently of one another selected from the    series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,-   or the groups R16 and R17, together with the nitrogen atom carrying    them, form a 5-membered to 6-membered, monocyclic saturated    heterocycle which, in addition to the nitrogen atom carrying R16 and    R17, comprises 0 or 1 further ring heteroatom selected from the    series consisting of nitrogen, oxygen and sulfur, and which is    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;-   R19 is selected from the series consisting of hydrogen,    (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-;-   R20 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₃-C₇)-cycloalkyl, HO—, oxo,    (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,    (HO)₂P(O)—O—, R16-N(R17)- and NC—;-   Het3 is a 5-membered to 10-membered monocyclic or bicyclic aromatic    heterocycle comprising 1 or 2 identical or different ring    heteroatoms selected from the series consisting of nitrogen, oxygen    and sulfur;-   wherein all cycloalkyl groups, independently of any other    substituents which can be present on a cycloalkyl group, can be    substituted by one or more identical substituents selected from the    series consisting of fluorine and (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents;-   in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and the pharmaceutically acceptable salt    thereof.

As another such example, compounds of the formula I may be mentioned,which are compounds of the formula Ie,

wherein

-   Ar is phenyl which is unsubstituted or substituted by one or more    identical or different substituents R1;-   R1 is selected from the series consisting of halogen, (C₁-C₆)-alkyl,    HO— and (C₁-C₆)-alkyl-O—;-   R2 is selected from the series consisting of R5-N(R6)-C(O)— and    R5-N(R6)-CH₂—;-   R3 is selected from the series consisting of hydrogen, halogen and    (C₁-C₄)-alkyl;-   R4 is hydrogen or one or more identical or different substituents    selected from the series consisting of halogen and (C₁-C₄)-alkyl;

one of the groups R5 and R6 is hydrogen and the other of the groups R5and R6 is selected from the series consisting of (C₁-C₆)-alkyl and(C₃-C₇)-cycloalkyl, wherein (C₁-C₆)-alkyl is unsubstituted orsubstituted by one or more identical or different substituents R10, and(C₃-C₇)-cycloalkyl is unsubstituted or substituted by one or moreidentical or different substituents R11;

-   R10 is selected from the series consisting of R14, fluorine, HO—,    (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,    (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)- and    R18-C(O)—N(R17)-;-   R11 is selected from the series consisting of (C₁-C₄)-alkyl,    HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-, fluorine, HO—,    (C₁-C₆)-alkyl-O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)- and    R18-C(O)—N(R17)-;-   R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring    which is saturated, partially unsaturated or aromatic and comprises    0, 1, 2 or 3 identical or different ring heteroatoms selected from    the series consisting of nitrogen, oxygen and sulfur, and which is    unsubstituted or substituted by one or more identical or different    substituents R20;-   R15 and R18 are independently of one another selected from the    series consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-;-   R16 and R17 are independently of one another selected from the    series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,-   or the groups R16 and R17, together with the nitrogen atom carrying    them, form a 5-membered to 6-membered, monocyclic saturated    heterocycle which, in addition to the nitrogen atom carrying R16 and    R17, comprises 0 or 1 further ring heteroatom selected from the    series consisting of nitrogen, oxygen and sulfur, and which is    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;-   R20 is selected from the series consisting of halogen,    (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₃-C₇)-cycloalkyl, HO—, oxo,    (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,    (HO)₂P(O)—O—, R16-N(R17)- and NC—;-   wherein all cycloalkyl groups, independently of any other    substituents which can be present on a cycloalkyl group, can be    substituted by one or more identical substituents selected from the    series consisting of fluorine and (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents;-   in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and the pharmaceutically acceptable salt    thereof.

As another such example, compounds of the formula I may be mentioned,which are compounds of the formula Ie,

wherein

-   Ar is phenyl which is unsubstituted or substituted by one or more    identical or different substituents R1;-   R1 is selected from the series consisting of halogen, (C₁-C₆)-alkyl,    HO— and (C₁-C₆)-alkyl-O—;-   R2 is selected from the series consisting of R5-N(R6)-C(O)— and    R5-N(R6)-CH₂—;-   R3 is selected from the series consisting of hydrogen, halogen and    (C₁-C₄)-alkyl;-   R4 is hydrogen or one or more identical or different substituents    selected from the series consisting of halogen and (C₁-C₄)-alkyl;

one of the groups R5 and R6 is hydrogen and the other of the groups R5and R6 is selected from the series consisting of (C₁-C₆)-alkyl and(C₃-C₇)-cycloalkyl, wherein (C₁-C₆)-alkyl is unsubstituted orsubstituted by one or more identical or different substituents R10, and(C₃-C₇)-cycloalkyl is unsubstituted or substituted by one or moreidentical or different substituents R11;

-   R10 is selected from the series consisting of fluorine, HO—,    (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,    (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)- and    R18-C(O)—N(R17)-;-   R11 is selected from the series consisting of (C₁-C₄)-alkyl,    HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-, fluorine, HO—,    (C₁-C₆)-alkyl-O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)- and    R18-C(O)—N(R17)-;-   R15 and R18 are independently of one another selected from the    series consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-;-   R16 and R17 are independently of one another selected from the    series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,-   or the groups R16 and R17, together with the nitrogen atom carrying    them, form a 5-membered to 6-membered, monocyclic saturated    heterocycle which, in addition to the nitrogen atom carrying R16 and    R17, comprises 0 or 1 further ring heteroatom selected from the    series consisting of nitrogen, oxygen and sulfur, and which is    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;-   wherein all cycloalkyl groups, independently of any other    substituents which can be present on a cycloalkyl group, can be    substituted by one or more identical substituents selected from the    series consisting of fluorine and (C₁-C₄)-alkyl;-   wherein all alkyl groups, independently of any other substituents    which can be present on an alkyl group, can be substituted by one or    more fluorine substituents;    in any of their stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, and the pharmaceutically acceptable salt    thereof.

A subject of the invention also is a compound of the formula I which isselected from any of the specific compounds of the formula I which aredisclosed herein, or is any one of the specific compounds of the formulaI which are disclosed herein, irrespective thereof whether they aredisclosed as a free compound and/or as a specific salt, or apharmaceutically acceptable salt thereof, wherein the compound of theformula I is a subject of the invention in any of its stereoisomericforms or a mixture of stereoisomeric forms in any ratio. For example, asubject of the invention is a compound of the formula I which isselected from the series consisting of:

-   2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    [2-(2-oxo-imidazolidin-1-yl)-ethyl]-amide,-   2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (2-hydroxy-ethyl)-amide,-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    cyclopropylamide,-   2-((S)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (2-hydroxy-ethyl)-amide,-   2-(2-Oxo-pyrrolidin-1-yl)-N-[2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-acetamide,-   Isoxazole-5-carboxylic acid    [2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide,-   2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    propylamide,-   4-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (isoxazol-5-ylmethyl)-amide,-   2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid (2-hydroxy-ethyl)-amide,-   2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid propylamide.-   Phosphoric acid    mono-(2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethyl)ester,-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-ylmethyl)-amide,-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid propylamide,-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (2-chloro-pyridin-4-ylmethyl)-amide,-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (1,5-dimethyl-1H-pyrazol-4-ylmethyl)-amide,-   1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid    [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide,-   2-((R)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (2-hydroxy-ethyl)-amide, and-   [2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-pyridin-4-ylmethyl-amine,-   or which is any one of these compounds, and its pharmaceutically    acceptable salts, wherein the compound of the formula I is a subject    of the invention in any of its stereoisomeric forms or a mixture of    stereoisomeric forms in any ratio, unless a specific stereoisomeric    form is specified with respect to any carbon atoms in the respective    compound.

Another subject of the invention is a compound of the formula I which isselected from the series consisting of:

-   2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    [2-(2-oxo-imidazolidin-1-yl)-ethyl]-amide,-   2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (2-hydroxy-ethyl)-amide,-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    cyclopropylamide,-   2-((S)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (2-hydroxy-ethyl)-amide,-   2-(2-Oxo-pyrrolidin-1-yl)-N-[2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-acetamide,-   Isoxazole-5-carboxylic acid    [2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide,-   2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    propylamide,-   4-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (isoxazol-5-ylmethyl)-amide,-   2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid (2-hydroxy-ethyl)-amide,-   2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid propylamide,-   Phosphoric acid    mono-(2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethyl)ester,-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-ylmethyl)-amide,-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid propylamide,-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (2-chloro-pyridin-4-ylmethyl)-amide,-   2-((R)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    (2-hydroxy-ethyl)-amide, and-   [2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-pyridin-4-ylmethyl-amine,-   or which is any one of these compounds, and its pharmaceutically    acceptable salts, wherein the compound of the formula I is a subject    of the invention in any of its stereoisomeric forms or a mixture of    stereoisomeric forms in any ratio, unless a specific stereoisomeric    form is specified with respect to any carbon atoms in the respective    compound.

In one embodiment of the invention, the compounds of the formula I aredefined as above in their generic definition or in any more specificdefinition or embodiment, with the proviso that the compound of theformula I is not one of the following compounds, which are namedaccording to the Chemical Abstracts system of nomenclature:

-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[1-(1,5-dimethyl-1H-pyrazol-4-yl)ethyl]-,-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-,-   1H-Pyrazole-4-sulfonamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1,3,5-trimethyl-,-   1H-Pyrazole-4-carboxamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1,5-dimethyl-,-   1H-Pyrazole-4-carboxamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1,3,5-trimethyl-,-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-,-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)methyl]-,-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[(1-methyl-1H-pyrazol-5-yl)methyl]-,-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-,-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-,-   1H-Pyrazole-4-sulfonamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1,5-dimethyl-,-   1H-Pyrazole-4-sulfonamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1-methyl-,-   1H-Pyrazole-3-carboxamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1-ethyl-,-   1H-Pyrazole-1-acetamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-,-   1H-Pyrazole-1-acetamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-3-methyl-,-   1H-Pyrazole-5-carboxamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1-ethyl-,-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[3-(1H-pyrazol-1-yl)propyl]-,-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[2-(3-methyl-1H-pyrazol-1-yl)ethyl]-,-   1H-Pyrazole-4-carboxamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1-ethyl-,-   5-Thiazolecarboxamide,    N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-6-yl]oxy]-,-   5-Thiazolecarboxamide,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-,-   1H-Pyrazole-1-propanamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-,-   1H-Pyrazole-4-sulfonamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-5-methyl-1-(1-methylethyl)-,-   5-Thiazolecarboxamide,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-,-   5-Thiazolecarboxamide,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[1-(1,5-dimethyl-1H-pyrazol-4-yl)ethyl]-,-   5-Thiazolecarboxamide,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[1-(1,3-dimethyl-1H-pyrazol-4-yl)ethyl]-,-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-,-   1H-Pyrazole-4-sulfonamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1-ethyl-,-   1H-Pyrazole-5-carboxamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1,3-dimethyl-,-   5-Thiazolemethanamine,    2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-N-[2-(1H-pyrazol-1-yl)ethyl]-,-   1H-Pyrazole-5-sulfonamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1-methyl-,-   1H-Pyrazole-5-carboxamide,    N-[[2-[(3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl)oxy]-5-thiazolyl]methyl]-1-methyl-,-   5-Thiazolecarboxamide,    N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-2-[[(2R)-2-(3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-6-yl]oxy]-,-   5-Thiazolecarboxamide,    N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-2-[[(2S)-2-(3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-6-yl]oxy]-,-   5-Thiazolecarboxamide,    2-[[(2R)-3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl]oxy]-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-,    and-   5-Thiazolecarboxamide,    2-[[(2S)-3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl]oxy]-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-,    wherein in the excluded compounds the carbon atom in position 2 of    the chroman ring, which carries a phenyl group or 3-fluorophenyl    group, is present in racemic form, unless specified otherwise, and    in another embodiment the excluded compounds are excluded as the    free compounds, i.e. not in the form of an addition salt with an    acid, and in the form of their 2,2,2-trifluoroacetates, i.e. their    acid addition salts with trifluoroacetic acid.

In another embodiment of the invention, the compounds of the formula Iare defined as above in their generic definition or in any of the morespecific definitions or embodiments, with the proviso that the compoundof the formula is not a compound in which simultaneously the group Ar isan unsubstituted phenyl group, the groups R3 and R4 are hydrogen, one ofthe groups R5 and R6 is hydrogen, the other of the groups R5 and R6 isR40-(C₁-C₄)-alkyl-, and R7 is R40 or R40-(C₁-C₄)-alkyl-, wherein R40 ispyrazolyl which is unsubstituted or substituted by one or more identicalor different (C₁-C₄)-alkyl substituents, and the carbon atom in position2 of the chroman ring which carries the group Ar is present in racemicform, and the proviso that the compound of the formula I is not one ofthe following compounds, which are named according to the ChemicalAbstracts system of nomenclature:

-   5-Thiazolecarboxamide.    N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-2-[[2-(3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-6-yl]oxy]-,-   5-Thiazolecarboxamide.    N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-2-[[(2R)-2-(3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-6-yl]oxy]-,-   5-Thiazolecarboxamide.    N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-2-[[(2S)-2-(3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-6-yl]oxy]-,-   5-Thiazolecarboxamide,    2-[[(2R)-3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl]oxy]-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-,    and-   5-Thiazolecarboxamide,    2-[[(2S)-3,4-dihydro-2-phenyl-2H-1-benzopyran-6-yl]oxy]-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-,    and in another embodiment the excluded compounds are excluded as the    free compounds, i.e. not in the form of an addition salt with an    acid, and in the form of their 2,2,2-trifluoroacetates, i.e. their    acid addition salts with trifluoroacetic acid.

In another embodiment of the invention, the compounds of the formula Iare defined as above in their generic definition or in any of the morespecific definitions or embodiments, provided that the compound of theformula I is not a compound in which simultaneously the group Ar isunsubstituted phenyl or 3-fluorophenyl, the groups R3 and R4 arehydrogen, one of the groups R5 and R6 is hydrogen, the other of thegroups R5 and R6 is R40-(C₁-C₄)-alkyl-, and R7 is R40 orR40-(C₁-C₄)-alkyl-, wherein R40 is pyrazolyl which is unsubstituted orsubstituted by one or more identical or different (C₁-C₄)-alkylsubstituents, and in another embodiment the excluded compounds areexcluded as the free compounds, i.e. not in the form of an addition saltwith an acid, and in the form of their 2,2,2-trifluoroacetates, i.e.their acid addition salts with trifluoroacetic acid.

Another subject of the present invention are processes for thepreparation of the compounds of the formula I which are outlined belowand by which the compounds of the formula I and intermediates occurringin the course of their synthesis are obtainable. For example, one suchprocess relates to the formation of compounds of the formula I fromchroman-6-ols of the formula II and 2-chloro-thiazoles of the formulaIII, and includes the linkage of the thiazole ring to the chroman ringto give compounds of the formula IV, and the subsequent conversion ofthe group Y into the group R2 that is attached to the thiazole ring inthe final compounds of the formula I.

The groups Ar, R3 and R4 in the compounds of the formulae II, III and IVare defined as in the compounds of the formula I, and additionally canfunctional groups be present in protected form or in the form of aprecursor group which is subsequently converted into the final group.The group Y in the compounds of the formulae III and IV, which group issubsequently transformed into the group R2 in the compound of theformula I, is selected from the series consisting of R50-O—C(O)—,H—C(O)— and NC—, wherein R50 is (C₁-C₄)-alkyl. The reaction of thecompounds of the formulae II and III is generally performed in an inertsolvent, in particular an aprotic solvent, for example an ether such astetrahydrofuran (THF), dioxane or 1,2-dimethoxyethane (DME) or an amidesuch as dimethylformamide (DMF), dimethylacetamide orN-methylpyrrolidin-2-one (NMP) in the presence of a base, for example abasic alkali metal salt like an alkali metal carbonate such as sodiumcarbonate, potassium carbonate or cesium carbonate, at temperatures fromabout 20° C. to about 100° C., in particular from about 40° C. to about60° C. In one embodiment of the invention, R50 is (C₁-C₂)-alkyl, forexample methyl or ethyl, in another embodiment it is tert-butyl.

Compounds of the formula IV in which the group Y is the groupR50-O—C(O)—, which are designated as compounds of the formula IVa, inparticular compounds of the formula IVa in which R50 is (C₁-C₂)-alkyl,can be reacted with amines of the formula V under standard conditionsfor the aminolysis of esters, for example in a solvent such as ahydrocarbon like toluene, a chlorinated hydrocarbon likedichloromethane, 1,2-dichloroethane or chlorobenzene or an ether likeTHF, dioxane or DME at temperatures from about 20° C. to about 120° C.,to give compounds of the formula I in which R2 is the groupR5-N(R6)-C(O)—, i.e. compounds of the formula Ia.

Compounds of the formula IV can also be transformed into compounds ofthe formula Ia in a convenient manner by first converting the compoundof the formula IVa into the respective carboxylic acid of the formulaVI, or a salt thereof, and reacting the compound of the formula VI orits salt with an amine of the formula V under standard conditions forthe formation of amides from carboxylic acids. The groups Ar, R3, R4, R5and R6 in the compounds of the formulae IVa, V and VI are defined as inthe compounds of the formula I, and additionally can functional groupsbe present in protected form or in the form of a precursor group whichis subsequently converted into the final group.

Compounds of the formula IVa can be converted into compounds of theformula VI by treatment with an acid or base, for example by treatmentwith an alkali metal hydroxide such as lithium hydroxide, sodiumhydroxide or potassium hydroxide in a solvent such as an ether like THF,dioxane or DME or an alcohol such as methanol or ethanol, or a mixtureof solvents, in particular an aqueous solvent or mixture of solvents, orby treatment with hydrochloric acid or trifluoroacetic acid in a solventsuch as a chlorinated hydrocarbon like dichloromethane, an ether or analcohol, in particular in the case of a tert-butyl ester, attemperatures from about 20° C. to about 100° C., followed by standardwork-up procedures such as an acidification in case the ester of theformula IVa is hydrolyzed in the presence of a base and a freecarboxylic acid of the formula VI is to be prepared, wherein thedetailed conditions depend on the particulars of the specific case, asusual, and are readily chosen by a person skilled in the art. For thereaction with the compound of the formula V, the carboxylic acid groupHO—C(O)— in the compound of the formula VI is generally activated insitu by means of a customary amide coupling reagent or converted into areactive carboxylic acid derivative which can be prepared in situ orisolated. For example, the compound of the formula VI can be convertedinto an acid halide, e.g. by treatment with thionyl chloride, phosphoruspentachloride or oxalyl chloride, or treated with an alkyl chloroformatelike ethyl chloroformate or isobutyl chloroformate to give a mixedanhydride. Customary coupling reagents which can be employed, arepropanephosphonic anhydride, N,N′-carbonyldiazoles likeN,N′-carbonyldiimidazole (CDI), carbodiimides like1,3-diisopropylcarbodiimide (DIC), 1,3-dicyclohexylcarbodiimide (DCC) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC),carbodiimides together with additives like 1-hydroxy-benzotriazole(HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT), uronium-based couplingreagents like O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) orO-(cyano(ethoxycarbonyl)methyleneamino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU), and phosphonium-based coupling reagents like(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP) or bromotripyrrolidinophosphoniumhexafluorophosphate (PyBroP). The reaction of the activated compound ofthe formula VI or a reactive derivative of the compound of the formulaVI is generally carried out in an inert solvent, for example ahydrocarbon like toluene, a chlorinated hydrocarbon likedichloromethane, an ether like THF, dioxane or DME, an ester like ethylacetate or butyl acetate, a nitrile like acetonitrile, an amide like DMFor NMP, or water, or a mixture of solvents, at temperatures from about−10° C. to about 100° C., in particular at temperatures from about 0° C.to about 60° C. Favorably, the reaction is carried out in the presenceof a base such as a tertiary amine, like triethylamine,ethyldiisopropylamine, N-methylmorpholine or pyridine, or an inorganicbase such as an alkali metal hydroxide, carbonate or hydrogencarbonate,like sodium hydroxide, potassium hydroxide, sodium carbonate or sodiumhydrogencarbonate.

Compounds of the formula IV in which the group Y is the group H—C(O)—,i.e. an aldehyde group or formyl group, which are designated ascompounds of the formula IVb, can be reacted with amines of the formulaV, in particular amines in which at least one of the groups R5 and R6 isdifferent from hydrogen, in a reductive amination reaction to givecompounds of the formula I in which R2 is the group R5-N(R6)-CH₂—, i.e.compounds of the formula Ib.

The groups Ar, R3 and R4 in the compounds of the formula IVb are definedas in the compounds of the formula I, and additionally can functionalgroups be present in protected form or in the form of a precursor groupwhich is subsequently converted into the final group. The reductiveamination can be carried out with a complex borohydride as reducingagent such as sodium cyanoborohydride or sodium triacetoxyborohydride,which can favorably be used also in polymer-bound form, in a solventsuch an ether like THF, dioxane or DME, an alcohol like methanol orethanol, or an acid like acetic acid, or a mixture of solvents, attemperatures from about 0° C. to about 70° C.

Compounds of the formula IV in which the group Y is the group NC—, i.e.a nitrile group or cyano group, which are designated as compounds of theformula IVc, can be reduced to aminomethyl compounds of the formula It,which can then be acylated with compounds of the formula VII andsulfonylated with compounds of the formula VIII to give furthercompounds of the formula I in which R2 is the group R7-C(O)—NH—CH₂— andthe group R7-S(O)₂—NH—CH₂—, respectively, i.e. compounds of the formulaeIc and Id.

The groups Ar, R3, R4 and R7 in the compounds of the formulae It, IVc,VII and VIII are defined as in the compounds of the formula I, andadditionally can functional groups be present in protected form or inthe form of a precursor group which is subsequently converted into thefinal group. The groups X1 and X2 in the compounds of the formulae VIIand VIII are nucleophilically substitutable leaving groups, inparticular chlorine, in which latter case the compounds of the formulaeVII and VIII are carboxylic acid chlorides and sulfonic acid chlorides.The groups X1 and X2 can also be a hydroxy group, in which case thecompounds of the formulae VII and VIII are carboxylic acids and sulfonicacids which are generally activated in situ by means of a customaryamide coupling reagent or converted into a reactive carboxylic acidderivative, such as the compound in which X1 or X2 is chlorine, for thereaction with the compound of the formula It. The explanations onactivating agents and reaction conditions given above with respect tothe reaction of the compounds of the formula VI with the compounds ofthe formula V to give carboxamides apply correspondingly to the reactionof the compounds of the formulae VII and VIII with the compounds of theformula It to give carboxamides and sulfonamides. The reduction of thenitrile group in the compounds of the formula IVc to the aminomethylgroup in the compounds of the formula It can be performed with variousreducing agents known to a person skilled in the art, such as complexmetal hydrides or boranes, or by catalytic hydrogenation in the presenceof a hydrogenation catalyst, for example Raney nickel, in a solvent suchas an ether like THF, dioxane or DME, an alcohol like methanol orethanol, or water or a mixture of solvents, at temperatures from about0° C. to about 80° C., the detailed conditions being dependent on thechosen reducing agent and the particulars of the specific case.

Compounds of the formula IV and It can be transformed into furthercompounds of the formula I also according to other synthetic strategies.For example, in case compounds of the formula Ib are to be prepared inwhich one of the groups R5 and R6 is hydrogen and the other is asubstituted methyl group, such as a group of the type R14-CH₂—, areductive amination reaction with a compound of the formula It and analdehyde of the formula R14-C(O)—H can be performed in a manner asdescribed above for the reaction of the compounds of the formulae IVband V. Compounds of the formulae Ib, Ic and Id can also be obtained byreducing a compound of the formula IVa or a compound of the formula IVbto the respective compound in which the group Y is a hydroxymethyl groupHO—CH₂—, converting the hydroxy group into a nucleophilicallysubstitutable leaving group such as chlorine or bromine or a sulfonyloxygroup like methanesulfonyloxy, and reacting the obtained alkylatingagent with an amine of the formula V, an amide of the formulaR7-C(O)—NH₂ or a salt thereof, or a sulfonamide of the formulaR7-S(O)₂—NH₂ or a salt thereof, respectively,

wherein in the compounds of the formulae R7-C(O)—NH₂ and R7-S(O)₂—NH₂the groups R7 are defined as in the compounds of the formula I andadditionally functional groups can be present in protected form or inthe form of a precursor group which is subsequently converted into thefinal group. Further, compounds of the formulae IVa, IVb, IVc and VI canbe converted into one another. If it is more convenient in a specificcase to react a compound of the formula II with a compound of theformula III in which Y is either R50-O—C(O)— or H—C(O)— or NC—, theobtained compound of the formula IV or a subsequently obtained compoundof the formula VI can be converted by standard procedures into compoundsof the formula IV in which Y has another meaning. For example, acarboxylic acid ester of the formula IVa or a nitrile of the formula IVccan be reduced to the aldehyde of the formula IVb, or a compound of theformula IVa or the formula VI can be converted into the carboxamide andthe latter dehydrated to the nitrile of the formula IVc, or an aldehydeof the formula IVb can be oxidized to a carboxylic acid of the formulaVI, or a nitrile of the formula IVc can be hydrolyzed to the carboxylicacid of the formula VI.

For obtaining further compounds of the formula I, varioustransformations of functional groups can be carried out under standardconditions in compounds of the formula I obtained as described above, orin intermediates or starting compounds in the synthesis of the compoundsof the formula I. For example, a hydroxy group can be reacted with acarboxylic acid or a reactive derivative thereof in a similar manner asdescribed above for the reaction of a carboxylic acid with an amine togive a carboxylic acid ester. Etherifications of hydroxy groups can beperformed by alkylation with the respective halogen compound, forexample a bromide or iodide, in the presence of a base such an alkalimetal carbonate like potassium carbonate or cesium carbonate in an inertsolvent such as an amide like DMF or NMP or a ketone like acetone orbutan-2-one, or with the respective alcohol under the conditions of theMitsunobu reaction in the presence of a phosphine liketriphenylphosphine or tributylphosphine and an azodicarboxylic acidderivative like diethyl azodicarboxylate or diisopropylazodicarboxylate. By reaction with an isocyanate, a hydroxy group can beconverted into an N-substituted carbamic acid ester. By treatment with asuitable halogenating agent, a hydroxy group can be converted into ahalide. By treatment with sulfur trioxide in the presence of pyridine, ahydroxy group can be converted into the sulfuric acid mono ester. Bytreatment with a suitable phosphoramidite, such as dibenzylN,N-diisopropyl-phosphoramidite, diallyl N,N-diisopropylphosphoramiditeor di-tert-butyl N,N-diisopropyl-phosphoramidite of the formula(Isopropyl)₂N—P(O—R55)₂, in which R55 is benzyl, allyl or tert-butyl,for example, in the presence of tetrazole and subsequent oxidation, forexample with a peracid like 3-chloro-perbenzoic acid, a hydroxy groupcan be converted into its phosphoric acid ester dibenzyl ester,phosphoric acid ester diallyl ester and phosphoric acid esterdi-tert-butyl ester, respectively, which can be cleaved to thephosphoric acid mono ester of the hydroxy group, i.e. the compound whichcontains the group (HO)₂P(O)— attached to the oxygen atom of the hydroxygroup, by catalytic hydrogenation in the presence of a palladiumcatalyst in the case of the dibenzyl ester, by a palladium-catalyzednucleophilic substitution in the case of the diallyl ester, and bytreatment with an acid such as trifluoroacetic acid in the case of thedi-tert-butyl ester. By treatment with chloromethyl chloroformate andsubsequently with silver dibenzylphosphate, a hydroxy group can beconverted into the carbonic acid ester dibenzyloxyphosphoryloxymethylester, which can be cleaved to the carbonic acid esterphosphonooxymethyl ester of the hydroxy group. i.e. the compound whichcontains the group (HO)₂P(O)—O—CH₂—O—C(O)-attached to the oxygen atom ofthe hydroxy group, by catalytic hydrogenation in the presence of apalladium Catalyst/cf. WO 2010/039474). A halogen atom can be replacedwith a variety of groups in a substitution reaction which may also be atransition-metal catalyzed reaction. An amino group can be modifiedunder standard conditions for alkylation, for example by reaction with ahalogen compound or by reductive amination of a carbonyl compound, orfor acylation or sulfonylation, for example by reaction with anactivated carboxylic acid or a carboxylic acid derivative like an acidchloride or anhydride. A carboxylic acid ester group can be hydrolyzedunder acidic or basic conditions to give a carboxylic acid. A carboxylicacid group can be activated or converted into a reactive derivative asoutlined above and reacted with an alcohol or an amine or ammonia togive an ester or amide. A primary amide can be dehydrated to give anitrile. A sulfur atom in an alkyl-S— group or in a heterocyclic ringcan be oxidized with a peroxide like hydrogen peroxide or a peracid togive a sulfoxide moiety (S(O)) or a sulfone moiety (S(O)₂). A carboxylicacid group, carboxylic acid ester group and a ketone group can bereduced to an alcohol, for example with a complex hydride such allithium aluminium hydride, lithium borohydride or sodium borohydride. Ahydroxy group can be oxidized to an oxo group by means of pyridiniumchlorochromate or the Dess-Martin periodinane reagent, for example. Allsuch reactions in the preparation of the compounds of the formula I areknown per se and can be carried out in a manner familiar to a personskilled in the art according to, or analogously, to procedures which aredescribed in the standard literature, for example in Houben-Weyl,Methods of Organic Chemistry, Thieme; or Organic Reactions, John Wiley &Sons; or R. C. Larock, Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2. ed. (1999), John Wiley & Sons, and thereferences quoted therein.

The chroman-6-ols of the formula II which are employed in the synthesisof the compounds of the formula IV described above, can be obtained bydifferent processes. In one of them, an acetophenone of the formula IX,which is substituted in the benzene ring by a hydroxy group and a groupG1 and can additionally be substituted in the benzene ring and theacetyl group by substituents R4, is condensed with an aldehyde of theformula X in the presence of a base to give a chroman-4-one of theformula XII and/or a chalcone of the formula XI, and an obtainedchalcone of the formula XI subsequently cyclized to the chroman-4-one ofthe formula XII.

The groups Ar and R4 in the compounds of the formulae IX, X, XI and XIIare defined as in the compounds of the formula I, and additionally canfunctional groups be present in protected form or in the form of aprecursor group which is subsequently converted into the final group.The group G1 in the compounds of the formulae IX, XI and XII is ahydroxy group or bromine. When performing the reaction of the compoundsof the formulae IX and X in the presence of an alkali metal hydroxidesuch as potassium hydroxide as the base in a solvent such as an alcohollike methanol or ethanol at temperatures from about 30° C. to about 70°C., the obtained product is the chalcone of the formula XI. Whenperforming the reaction of the compounds of the formulae IX and X in thepresence of a salt of a weak acid such as ammonium acetate, for example,in a solvent such as acetic acid at temperatures from about 100° C. toabout 120° C., the obtained product is a mixture of the chalcone of theformula XI and chroman-4-one of the formula XII. The compound of theformula XI, as well as a mixture of the compounds of the formulae XI andXII, can be employed in the cyclization reaction to give the compound ofthe formula XII, which can be carried out by treating the startingmaterial with an acid like hydrochloric acid or with an amine likeethyldiisopropylamine and potassium fluoride, in a solvent such as analcohol like methanol or ethanol at temperatures from about 60° C. toabout 100° C.

The oxo group in the ring position 4 of the compounds of the formula XIIis then reduced to a CH₂ group to give the compounds of the formula XIV,favorably stepwise via the 4-hydroxy-chroman derivatives of the formulaXIII.

The groups Ar and R4 in the compounds of the formulae XIII and XIV aredefined as in the compounds of the formula I, and additionally canfunctional groups be present in protected form or in the form of aprecursor group which is subsequently converted into the final group.The group G1 in the compounds of the formulae XIII and XIV is a hydroxygroup or bromine. The reduction of the compounds of the formula XII tothe compounds of the formula XIII can be carried out under standardconditions for the reduction of a ketone to an alcohol, for example bymeans of a complex hydride as reducing agent, or a borane derivative,such as the borane-tetrahydrofuran complex in a solvent such as an etherlike THF or dioxane, at temperatures from about 30° C. to about 80° C.The reduction of the compounds of the formula XIII to the compounds ofthe formula XIV can be performed, for example, by treatment with asilane reducing such as a trialkylsilane like triethylsilane and an acidsuch as trifluoroacetic acid in a solvent such as a chlorinatedhydrocarbon like dichloromethane at temperatures from about 0° C. toabout 40° C. In case the group G1 in the compound of the formula XIIIand its precursor compounds is a hydroxy group, the obtained compound ofthe formula XIV already is a compound of the formula II. In case thegroup G1 in the obtained compound of the formula XIV is bromine, it canbe converted into a hydroxy group by metalation of the compound of theformula XIV with a organolithium compound such as butyllithium andtreatment with a trialkyl borate such as triisopropyl borate in asolvent such as a hydrocarbon like heptane or cyclohexane or an etherlike THF or dioxane at temperatures from about −80° C. to about 0° C.,followed by oxidative cleavage, for example by means of hydrogenperoxide in the presence of a base such as sodium hydroxide.

Further processes for the preparation of chroman-6-ols of the formula IIinvolve a cyclization of 3-hydroxypropyl-substituted benzene derivativeof the formula XV, which is substituted in the benzene ring by twosuitable groups G2 and G3 and can additionally be substituted in thebenzene ring and the propyl group by substituents R4, to give a chromanderivative of the formula XVI, in which the group G3 is then convertedinto the hydroxy group present in the compounds of the formula

The groups Ar and R4 in the compounds of the formulae XV and XVI aredefined as in the compounds of the formula I, and additionally canfunctional groups be present in protected form or in the form of aprecursor group which is subsequently converted into the final group.The group G2 in the compounds of the formula XV can be a hydroxy groupor a nucleophilically substitutable leaving group, for example fluorine.The group G3 in the compounds of the formulae XV and XVI can be bromineor (C₁-C₄)-alkyl-O— such as methoxy, for example. In case G3 is bromine,the conversion of the group G3 in the compound of the formula XVI intothe hydroxy group in the compound of the formula II can be performed asdescribed above for the conversion of the compounds of the formula XIVinto the compounds of the formula II. In case G3 is (C₁-C₄)-alkyl-O—,the conversion into the hydroxy group can be performed according tostandard procedures for ether cleavage, for example by treatment withboron tribromide in a chlorinated hydrocarbon such as dichloromethane attemperatures from about −20° C. to about 10° C. in the case of a methoxygroup. In case the group G2 is a hydroxy group, the cyclization of thecompound of the formula XV to the compound of the formula XVI canconveniently be performed under the conditions of Mitsunobu reaction bytreatment with a phosphine such as triphenylphosphine ortributylphosphine and an azodicarboxylic acid derivative such as diethylazodicarboxylate or diisopropyl azodicarboxylate in a solvent such as anether like THF or dioxane at temperatures from about 0° to about 30° C.In case the benzene ring carrying G2 in the compound of the formula XVis susceptible to a nucleophilic aromatic substitution and G2 is aleaving group such as fluorine, the cyclization can be performed bytreatment of the compound of the formula XV with a base which enhancesthe nucleophilicity of the hydroxy group in position 3 of the propylgroup, for example an alkali metal amide or an alkali metal hydride likesodium hydride, in an inert solvent such as an ether like THF or dioxaneor an amide like DMF or NMP at temperatures from about −20° C. to about100° C.

By cyclization of compounds of the formula XV also individualstereoisomeric forms of the compounds of the formula XVI and II, andfinally of compounds of the formula I, can be conveniently be preparedin which the chiral carbon atom in position 2 of the chroman ring systemis present either in R configuration or in S configuration. For thesynthesis of such individual stereoisomers, which can otherwise beobtained, for example, by chromatographic resolution on a chiral phaseof a mixture of the stereoisomers of the final compounds of the formulaI or at any stage of the synthesis, the individual stereoisomeric formsof the 3-hydroxypropyl-substituted benzene of the formula XV areemployed, i.e. the compounds of the formula XVa. Depending on thecyclization reaction and the conditions chosen, the cyclization canproceed with retention or inversion of the configuration of the chiralcarbon atom to give the individual stereoisomeric forms of the compoundsof the formula XVI, i.e. the compounds of the formula XVIa, which can bereacted further to the individual stereoisomeric forms compounds of theformulae II and I. In the compounds of the formulae XVa and XVIa are thegroups Ar, R4, G2 and G3 defined as in the compounds of the formula XVand XVI, respectively, and the depicted chiral carbon atom is present,or is essentially present, either in R configuration or in Sconfiguration, as is indicated by the wavy wedge.

One embodiment of the present invention thus relates to a process forthe preparation of a compound of the formula I,

which comprises cyclizing a compound of the formula XV to a compound ofthe formula XVI, converting the compound of the formula XVI into acompound of the formula II, reacting the compound of the formula II witha compound of the formula III to give a compound of the formula IV, andconverting the compound of the formula IV into a compound of the formulaI, wherein the groups Ar, R3 and R4 in the compounds of the formulae II,III, IV, XV and XVI are defined as in the compounds of the formula I,and additionally can functional groups be present in protected form orin the form of a precursor group which is subsequently converted intothe final group, the group G2 in the compound of the formula XV is ahydroxy group or a nucleophilically substitutable leaving group, forexample fluorine, the group G3 in the compounds of the formulae XV andXVI is bromine or (C₁-C₄)-alkyl-O—, and the group Y in the compounds ofthe formulae III and IV is R50-O—C(O)—, H—C(O)— or NC—, wherein R50 is(C₁-C₄)-alkyl.

Another embodiment of the present invention relates to the processdescribed afore, in which the chiral carbon atom carrying the group Arin the compounds of the formulae II, IV, XV and XVI is present, or isessentially present, in uniform configuration, either in R configurationor in S configuration, i.e. to a process for the preparation of acompound of the formula Iq,

which comprises cyclizing a compound of the formula XVa to a compound ofthe formula XVIa, converting the compound of the formula XVIVa into acompound of the formula IIa, reacting the compound of the formula IIawith a compound of the formula III to give a compound of the formulaIVd, and converting the compound of the formula IVd into a compound ofthe formula Iq, wherein the groups Ar, R2, R3 and R4 in the compounds ofthe formulae Iq, IIa, III, IVd, XVa and XVIa are defined as in thecompounds of the formula I, and additionally can functional groups bepresent in protected form or in the form of a precursor group which issubsequently converted into the final group, the group G2 in thecompound of the formula XVa is a hydroxy group or a nucleophilicallysubstitutable leaving group, for example fluorine, the group G3 in thecompounds of the formulae XVa and XVIa is bromine or (C₁-C₄)-alkyl-O—,and the group Y in the compounds of the formulae III and IVd isR50-O—C(O)—, H—C(O)— or NC—, wherein R50 is (C₁-C₄)-alkyl, wherein thechiral carbon atom carrying the group Ar in the compounds of theformulae Iq, IIa, IVd, XVa and XVIa is present, or is essentiallypresent, in uniform configuration, either in R configuration or in Sconfiguration.

The compounds of the formula XV, including the stereoisomeric forms ofthe formula XVa, which are employed in the cyclization reaction to thecompounds of the formulae XVI and XVIa described above, can be obtainedaccording to, or analogously to, various processes which are describedin the literature. For example, a 3-oxo-propionic acid ester of theformula XVII can be alkylated with a benzyl halide of the formula XVIIIto give a 3-oxo-propyl-substituted benzene derivative of the formulaXIX, in which the ketone group is then reduced to the alcohol group togive a compound of the formula XV.

The groups Ar and R4 in the compounds of the formulae XVII, XVIII andXIX are defined as in the compounds of the formula I, and additionallycan functional groups be present in protected form or in the form of aprecursor group which is subsequently converted into the final group. Inthe preparation of compounds of the formula XV according to thisprocess, the group G2 in the compounds of the formulae XVIII and XIX isin particular a nucleophilically substitutable leaving group, forexample fluorine, and the group G3 in the compounds of the formulaeXVIII and XIX in particular is bromine. The group R51 in the compoundsof the formula XVII is (C₁-C₄)-alkyl, for example methyl or ethyl. Thegroup X3 in the compounds of the formula XVIII is a nucleophilicallysubstitutable leaving group, for example chlorine or bromine. Thereaction of the compounds of the formulae XVII and XVIII to give thecompounds of the formula XIX is performed in an inert solvent such as anether like THF, dioxane or DME in the presence of base such as an alkalimetal alkoxide or an alkali metal hydride, for example sodium hydride,at temperatures from about 0° C. to about 50° C. By treatment of theobtained benzylated 3-oxo-propionic acid ester with an acid, for examplehydrochloric acid in an aqueous solvent such as an ether like dioxane oran acid like acetic acid or a mixture of solvents at temperatures fromabout 60° C. to about 120° C. the ester moiety is then saponified anddecarboxylated to give the ketone of the formula XIX. For the reductionof the ketone moiety in the compounds of the formula XIX to thecompounds of the formula XV, various reducing agents can be employed,for example complex metal hydride such as sodium borohydride or lithiumborohydride in a solvent such as an ether or an alcohol. In anasymmetric reduction reaction, by employing a chiral reducing agent, forexample an enantiomeric form of a chiral complex metal hydride or achiral borane, such as an alpha-pinene-based organoborane likeB-chloro-diisopinocampheylborane, which is commonly abbreviated as(−)-Ipc₂BCl or (−)-DipCl, and (+)-Ipc₂BCl or (+)-DipCl, respectively, inan inert solvent such as an ether like THF or dioxane at temperaturesfrom about −40° C. to about 30° C., conveniently the individualstereoisomeric forms of the compounds of the formula XV can be obtained,i.e. compounds of the formula XVa, which can be cyclized to theenantiomeric forms of the compounds of the formula XVI, i.e. thecompounds of the formula XVIa, as described above.

In another process for the preparation of compounds of the formula XV,an indan-1-one of the formula XX is subjected to a ring enlargement togive a chroman-2-one of the formula XXI, in which the lactone moiety canbe reduced to an aldehyde moiety which is present in the form of thecyclic hemiacetal of the formula XXII and which can be reacted with asuitable organometal compound of the formula XXIII.

The groups Ar and R4 in the compounds of the formulae XX, XXI, XXII andXXIII are defined as in the compounds of the formula I, and additionallycan functional groups be present in protected form or in the form of aprecursor group which is subsequently converted into the final group. Inthe preparation of compounds of the formula XV according to thisprocess, the group G3 in the compounds of the formulae XX. XXI and XXIIis in particular a (C₁-C₄)-alkyl-O— group. The group M in the compoundsof the formula XXIII is a metal or a metal equivalent, for examplelithium. The conversion of the compound of the formula XX into thecompound of the formula XXI can be performed by treatment with a peracidsuch as 3-chloro-perbenzoic acid in a solvent such as a chlorinatedhydrocarbon like dichloromethane at temperatures from about −10° C. toabout 30° C. For the reduction of the lactone moiety in the compound ofthe formula XXI to the masked aldehyde moiety in the compound of theformula XXII, a complex metal reducing agent can be used, such asdiisobutylaluminum hydride, in a solvent such as a hydrocarbon likecyclohexane or toluene or a chlorinated hydrocarbon like dichloromethaneor an ether like THF or dioxane, or a mixture of solvents, attemperatures from about −80° C. to about 30° C. For the subsequent step,the compound of the formula XXIII is generally prepared in situ from asuitable respective benzene or aromatic heterocycle orhalogen-substituted benzene or halogen-substituted aromatic heterocycleby metalation, for example with an organolithium compound likebutyllithium or a lithium amide like lithium diisopropylamide or lithium2,2,6,6-tetramethylpiperidide, and reacted with the compound of theformula XXII in an inert solvent such as a hydrocarbon like heptane orcyclohexane or an ether like THF or a mixture of solvents attemperatures from about −80° C. to about 30° C.

As already indicated, it can be advantageous or necessary in allreactions which are carried out in the course of the preparation of thecompounds of the formula I to temporarily protect functional groups orhave them initially present in the form of precursor groups, and laterdeprotect them or convert them into the desired groups. Appropriatesynthesis strategies and protective groups and precursor groups whichare suitable for the respective case, are known to the person skilled inthe art and can be found in P. G. M. Wuts and T. W. Greene, Greene'sProtective Groups in Organic Synthesis, 4. ed. (2007), John Wiley &Sons, for example. Examples of protective groups which may be mentioned,are benzyl protective groups, for example benzyl ethers of hydroxycompounds and benzyl esters of carboxylic acids, from which the benzylgroup can be removed by catalytic hydrogenation in the presence of apalladium catalyst, tert-butyl protective groups, for example tert-butylesters of carboxylic acids, from which the tert-butyl group can beremoved by treatment with trifluoroacetic acid, acyl protective groups,for example ester and amides of hydroxy compounds and amino compounds,which can be cleaved again by acidic or basic hydrolysis, oralkoxycarbonyl protective groups, for example tert-butoxycarbonylderivatives of amino compounds, which can be cleaved again by treatmentwith trifluoroacetic acid. Examples of precursors which may be mentionedare halogen atoms which can be replaced by many other groups, or nitrogroups which can be converted, for example by catalytic hydrogenation,into amino groups which can be diazotized and converted into a largenumber of groups.

The starting materials employed in the procedures outlined above arecommercially available or can be prepared according to procedures, or inanalogy to procedures, described in the literature. Procedures for thepreparation of 2-chloro-thiazole derivatives of the formula III, forexample, are described in U.S. Pat. No. 4,168,380, WO 01/17995 or I.Sawhney et al., J. Chem. Soc. Perkin Trans. 1 (1990), 329-331, forexample.

As is usual and applies to all reactions performed in the course of thesynthesis of a compound of the formula I, appropriate details of theconditions applied in a specific preparation process, including thesolvent, a base or acid, the temperature, the order of addition, themolar ratios and other parameters, are routinely chosen by the skilledperson in view of the characteristics of the starting compounds and thetarget compound and the other particularities of the specific case. Asis also known by the skilled person, not all processes described hereinwill in the same way be suitable for the preparation of all compounds ofthe formula I and their intermediates, and adaptations have to be made.In all processes for the preparation of the compounds of the formula I,workup of the reaction mixture and the purification of the product isperformed according to customary methods known to the skilled personwhich include, for example, quenching of a reaction mixture with water,adjustment of a certain pH, precipitation, extraction, drying,concentration, crystallization, distillation and chromatography. Alsofor the characterization of the product, customary methods are used suchas NMR, IR and mass spectroscopy.

Another subject of the present invention are the novel startingcompounds and intermediates occurring in the synthesis of the compoundsof the formula I, including the compounds of the formulae II, III, IV,IVa, IVb, IVc, IVd, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV,XVa, XVI, XVIa, XVII, XVIII, XIX, XX, XXI, XXII and XXIII, wherein thegroups Ar, R2, R3, R4, R5, R6, R7, R50, R51, G1, G2, G3, M, X1, X2, X3and Y are defined as above, in any of their stereoisomeric forms or amixture of stereoisomeric forms in any ratio, and their salts, and theiruse as synthetic intermediates or starting compounds. All generalexplanations, specifications of embodiments and definitions of numbersand groups given above with respect to the compounds of the formula Iapply correspondingly to the said intermediates and starting compounds.A subject of the invention are in particular the novel specific startingcompounds and intermediates described herein. Independently thereofwhether they are described as a free compound and/or as a specific salt,they are a subject of the invention both in the form of the freecompounds and in the form of their salts, and if a specific salt isdescribed, additionally in the form of this specific salt.

The compounds of the formula I inhibit the sodium-calcium exchanger(NCX), especially the sodium-calcium exchanger of subtype 1 (NCX1), ascan be demonstrated in the pharmacological tests described below and inother pharmacological tests which are known to a person skilled in theart, for example in animal models in which the effect on heart functioncan be determined ex vivo or in vivo. The compounds of the formula I andtheir pharmaceutically acceptable salts therefore are valuablepharmaceutical active compounds. The compounds of the formula I andtheir pharmaceutically active salts can be used for the treatment ofheart failure, including acute and chronic congestive heart failure,systolic head failure, diastolic heart failure, heart failure withpreserved ejection fraction and diabetic heart failure, cardiacarrhythmias including atrial fibrillation, stroke, dementia includingAlzheimer's Disease, hypertension, cardiac ischemia, renal failure,shock including hemodynamic shock, cardiogenic shock and septic shock,age-related disorders, and diseases which are caused secondarily by anNCX-related damage, for example. The treatment of diseases is to beunderstood as meaning both the therapy of existing pathological changesor malfunctions of the organism or of existing symptoms with the aim ofrelief, alleviation or cure, and the prophylaxis or prevention ofpathological changes or malfunctions of the organism or of symptoms inhumans or animals which are susceptible thereto and are in need of sucha prophylaxis or prevention, with the aim of a prevention or suppressionof their occurrence or of an attenuation in the case of theiroccurrence. For example, in patients who on account of their diseasehistory are susceptible to cardiac arrhythmias, by means of theprophylactic or preventive medicinal treatment the occurrence orre-occurrence of arrhythmias can be prevented or their extent andsequelae decreased. The treatment of diseases can occur both in acutecases and in chronic cases. The compounds of the formula I and theirpharmaceutically acceptable salts can further be used in variousdisorders in order to achieve an improvement of the perfusion of heart,brain and kidney, and in general in disorders in which intracellularcalcium homeostasis is disturbed, or the NCX is activated in anundesired manner, or an inhibition of the NCX is intended by thephysician for improving the patient's condition, where the compounds ofthe formula I and their pharmaceutically acceptable salts can also beemployed in cases where only a certain partial inhibition of the NCX isintended, for example by use of a low dosage.

The compounds of the formula I and their pharmaceutically acceptablesalts can therefore be used in animals, in particular in mammals andspecifically in humans, as a pharmaceutical or medicament on their own,in mixtures with one another, or in the form of pharmaceuticalcompositions. A subject of the present invention also are the compoundsof the formula I and their pharmaceutically acceptable salts for use asa pharmaceutical. A subject of the present invention also arepharmaceutical compositions and medicaments which comprise at least onecompound of the formula I and/oro pharmaceutically acceptable saltthereof as an active ingredient, in an effective dose for the desireduse, and a pharmaceutically acceptable carrier, i.e. one or morepharmaceutically innocuous, or nonhazardous, vehicles and/or excipients,and optionally one or more other pharmaceutical active compounds. Asubject of the present invention also are the compounds of the formula Iand their pharmaceutically acceptable salts for use as ananti-arrhythmic. A subject of the present invention also are thecompounds of the formula I and their pharmaceutically acceptable saltsfor use in the treatment of the diseases mentioned above or below,including the treatment of any one of the mentioned diseases, forexample heart failure, cardiac arrhythmias, stroke, dementia,hypertension, cardiac ischemia, renal failure, shock, age-relateddisorders or diseases which are caused secondarily by an NCX-relateddamage, wherein treatment of diseases comprises their therapy andprophylaxis as mentioned above, or for use an inhibitor of the NCX. Asubject of the present invention also are the use of the compounds ofthe formula I and their pharmaceutically acceptable salts for themanufacture of a medicament for the treatment of the diseases mentionedabove or below, including the treatment of any one of the mentioneddiseases, for example heart failure, cardiac arrhythmias, stroke,dementia, hypertension, cardiac ischemia, renal failure, shock,age-related disorders or diseases which are caused secondarily by anNCX-related damages, wherein treatment of diseases comprises theirtherapy and prophylaxis as mentioned above, or a medicament forinhibition of the NCX. A subject of the present invention also aremethods for the treatment of the diseases mentioned above or below,including the treatment of any one of the mentioned diseases, forexample heart failure, cardiac arrhythmias, stroke, dementia,hypertension, cardiac ischemia, renal failure, shock, age-relateddisorders or diseases which are caused secondarily by an NCX-relateddamage, wherein treatment of diseases comprises their therapy andprophylaxis as mentioned above, and a method for inhibiting the NCX,which comprise administering an efficacious amount of at least onecompound of the formula I and/or a pharmaceutically acceptable saltthereof to a human or an animal which is in need thereof. The compoundsof the formula I and their pharmaceutically acceptable salts, andpharmaceutical compositions and medicaments comprising them, can beadministered enterally, for example by oral or rectal administration,parenterally, for example by intravenous, intramuscular or subcutaneousinjection or infusion, or by another type of administration such astopical, percutaneous, transcutaneous, nasal, pharyngeal or inhalativeadministration, the preferred form of administration depending on theparticulars of the specific case. The compounds of the formula I andtheir pharmaceutically acceptable salts can also be used in combinationwith other pharmaceutical active compounds.

The pharmaceutical compositions and medicaments according to theinvention normally contain from about 0.5 to about 90 percent by weightof a compound or compounds of the formula I or pharmaceuticallyacceptable salts thereof, and an amount of active ingredient of theformula I and/or its pharmaceutically acceptable salt which in generalis from about 0.1 mg to about 1 g, in particular from about 0.2 mg toabout 500 mg, for example from about 1 mg to about 300 mg, per doseunit. Depending on the kind of the pharmaceutical composition and otherparticulars of the specific case, the amount may deviate from theindicated ones. The production of the pharmaceutical compositions andmedicaments can be carried out in a manner known per se and familiar tothe person skilled in the art. For this, the compounds of the formula Iand/or their pharmaceutically acceptable salts are mixed together withone or more solid or liquid vehicles and/or excipients, if desired alsoin combination with one or more other pharmaceutical active compounds,and brought into a suitable form for dosage and administration, whichcan then be used in human medicine or veterinary medicine.

As vehicles, which may also be looked upon as diluents or solvents orbulking agents, and excipients suitable organic and inorganic substancescan be used which do not react in an undesired manner with the compoundsof the formula I. As examples of types of excipients, or additives,which can be contained in the pharmaceutical compositions andmedicaments, lubricants, preservatives, gel formers, thickeners,stabilizers, disintegrants, wetting agents, emulsifiers, dispersants,antifoaming agents, salts, buffer substances, colorants, flavorings andantioxidants may be mentioned. Examples of vehicles and excipients arewater, physiological saline, vegetable oils such as sunflower oil,animal oils such as fish liver oil, waxes, alcohols such as ethanol,isopropanol, 1,2-propanediol, glycerol, polyols, polyethylene glycols,polyvinylpyrrolidone, gelatin, gum arabic, cellulose, carbohydrates suchas glucose, lactose or starch like corn starch, magnesium carbonate,potassium phosphate, sodium chloride, stearic acid and its salts such asmagnesium stearate, talc, lanolin, petroleum jelly, or mixtures thereof,for example mixtures of water or saline with one or more organicsolvents such as mixtures of water with alcohols.

For oral and rectal use, pharmaceutical forms such as, for example,tablets, coated tablets, sugar-coated tablets, granules, hard and softgelatin capsules, suppositories, solutions, including oily, alcoholic oraqueous solutions, or drops, furthermore suspensions or emulsions, canbe used. For parenteral use, for example by injection or infusion,pharmaceutical forms such as solutions, for example aqueous solutions,can be used. For topical use, pharmaceutical forms such as ointments,creams, pastes, lotions, gels, sprays, foams, aerosols, solutions orpowders can be used. Pharmaceutical formulations such as, for example,aerosols and sprays may comprise solutions, suspensions or emulsions ofthe active ingredient in a pharmaceutically acceptable solvent, such asethanol or water, or a mixture of such solvents. The formulation mayalso comprise other pharmaceutical excipients such as surfactants,emulsifiers and stabilizers, and a propellant gas. Such a pharmaceuticalform normally comprises the active ingredient in a concentration ofabout 0.1 to about 10%, in particular of about 0.3 to about 3% byweight.

As usual, the dosage of the compounds of the formula I and the frequencyof administration depend on the circumstances of the specific case andis adjusted by the physician according to the customary rules andprocedures. It depends, for example, on the compound of the formula Iadministered and its potency and duration of action, on the nature andseverity of the individual syndrome, on the gender, age, weight and theindividual responsiveness of the human or animal to be treated, onwhether the treatment is acute or chronic or prophylactic, or on whetherfurther pharmaceutical active compounds are administered in addition toa compound of the formula I. Normally, in the case of administration toan adult weighing about 75 kg, a dose from about 0.1 mg to about 100 mgper kg per day, in particular from about 1 mg to about 10 mg per kg perday (in each case in mg per kg of body weight), is sufficient. The dailydose can be administered in the form of a single dose or divided into anumber of individual doses, for example two, three or four individualdoses. The administration can also be carried out continuously, forexample by continuous injection or infusion. Depending on the individualbehavior in a specific case, it may be necessary to deviate upward ordownward from the indicated dosages.

Besides as a pharmaceutical active compound in human medicine andveterinary medicine, the compounds of the formula I can also be employedas an aid in biochemical investigations or as a scientific tool or fordiagnostic purposes, for example in in vitro diagnoses of biologicalsamples, if an inhibition of the NCX is intended. The compounds of theformula I and their salts can also be used as intermediates for thepreparation of further pharmaceutical active substances.

The following examples illustrate the invention.

When example compounds containing a basic group were purified bypreparative high pressure liquid chromatography (HPLC) on reversed phase(RP) column material and, as customary, the eluent was a gradientmixture of water and acetonitrile containing trifluoroacetic acid, theywere in part obtained in the form of their acid addition salts withtrifluoroacetic acid, depending on the details of the workup such asevaporation or lyophilization conditions. In the names of the examplecompounds and the structural formulae such contained trifluoroaceticacid is not specified.

The prepared compounds were in general characterized by spectroscopicdata and chromatographic data, in particular mass spectra (MS) and HPLCretention times (Rt; in min) which were obtained by combined analyticalHPLC/MS characterization (LC/MS), and/or nuclear magnetic resonance(NMR) spectra. Unless specified otherwise, ¹H-NMR spectra were recordedat 500 MHz in D₆-DMSO as solvent at 298 K. In the NMR characterization,the chemical shift δ (in ppm), the number of hydrogen atoms (H) and themultiplicity (s: singlet, d: doublet, dd: double doublet, t: triplet, m:multiplet; br: broad) of the peaks as determined on printouts are given.In the MS characterization, in general the mass number (m/z) of the peakof the molecular ion [M], e.g. [M⁺], or of a related ion such as the ion[M+1], e.g. [(M+1)⁺], i.e. the protonated molecular ion [(M+H)⁺]([MH⁺]), or the ion [M−1], e.g. [(M−1)⁻], i.e. the deprotonatedmolecular ion [(M−H)⁻], which was formed depending on the ionizationmethod used, is given. Generally, the ionization method was electrosprayionization (ESI⁺). The UV wavelength for HPLC detection generally was220 nm. The particulars of the LC/MS methods used are as follows. “ACN”means acetonitrile, “TFA” means trifluoroacetic acid, and “FA” means“formic acid.

Method A

Column: Waters XBridge C18, 3.5 μm, 3×100 mm; temperature: 55° C.;eluent A: water+0.05% TFA (trifluoroacetic acid); eluent B: ACN(acetonitrile)+0.05% TFA; flow rate: 1 ml/min; gradient: from 5% of B to95% of B in 5 min.

Method B

Column: WatersXBridge C18, 2.5 μm, 4.6×50 mm; temperature: 50° C.;eluent A: water+0.05% TFA; eluent B: ACN+0.05% TFA; flow rate: 1.7ml/min; gradient: 5% B for 0.2 min, then to 95% of B in 2.2 min, then95% of B for 1.1 min, then to 5% of B in 0.1 min, then 5% of B for 0.9min.

Method C

Column: Atlantis T3 C18, 3 μm, 3×100 mm; temperature: 55° C.; eluent A:water+0.05% TFA; eluent ACN+0.05% TEA; flow rate: 1 ml/min; gradient:from 5 of B to 95% of B in 5 min.

Method D

Column: Acquity BEH C18, 1.7 μm, 2.1×50 mm; temperature: 40° C.; eluentA: water+0.05% TFA; eluent B: ACN+0.035% TFA; flow rate: 1.0 ml/min;gradient: from 2% of B to 100% of B in 1.6 min, then 100% of B for 0.5min, then to 2% of B in 0.4 min, then 2% of B for 0.5 min.

Method E

Column: Merck Chromolith FastGrad RP-18e, 1.6 μm, 2×50 mm; temperature:50° C.; eluent A: water+0.05% TFA; eluent ACN+0.05% TFA; flow rate: 2.0ml/min; gradient: 2% of B for 0.2 min, then to 98% of B in 2.2 min, then98% of B for 0.8 min, then to 2% of B in 0.1 min, then 2% of B for 0.7min.

Method F

Column: Kromasil C18, 3.5 μm, 2×50 mm; temperature: 40° C.; eluent A; 5mM aqueous ammonium acetate solution+3% of ACN; eluent B: ACN; flowrate: 0.8 ml/min; gradient: from 0% of B to 100% of B in 5.5. min, 100%of B for 1.5 min, then to 0% of B in 0.1 min, then 0% of B for 2.9 min.

Method G

Column: YMC-Pack Jsphere H80, 4 μM, 2.1×33 mm; temperature: roomtemperature; eluent A: water+0.05% TFA; eluent B: ACN+0.05% TFA; flowrate: 1 ml/min; gradient: 2% of B for 1.0 min, then to 95% of B in 4min, then 95% of B for 1.25 min.

Method H

Column: Waters UPLC BEH C18, 1.7 μm, 2.1×50 mm; temperature: 55° C.;eluent A: water+0.1% FA; eluent B: ACN+0.08% FA; flow rate: 0.9 ml/min;gradient: from 5% of B to 95% of B in 1.1 min, then 95% of B for 0.6min, then to 596 of B in 0.1 min, then 5% of B for 0.2 min.

Method I

Column: Waters BEH C18, 1.7 μm, 2.1×50 mm; temperature: 50° C.; eluentA: water+0.1% FA; eluent ACN+0.1% FA; gradient: from 5% of B to 6% of Bin 0.05 min, then to 100% of B in 2.45 min.

Method J

Column: Waters XBridge C18, 2.5 μm, 4.6×50 mm; temperature: 45° C.;eluent A: water+0.1% FA; eluent B: ACN+0.1% FA; flow rate: 1.3 ml/min;gradient: from 3% of B to 60% of B in 3.5 min, then to 98% of B in 0.5min, then 98% of B for 1 min, then to 3% of B in 0.2 min, then 3% of Bfor 1.3 min.

Method K

Column: Waters UPLC BEH C18 2, 1.7 μm, 1×50 mm; temperature: 55° C.;eluent A: water+0.05% FA; eluent B: ACN+0.035% FA; flow rate: 0.9ml/min; gradient: from 5% of B to 95% of B in 1.1 min, then 95% of B for0.6 min, then to 5% of B in 0.1 min, then 5% of B for 0.2 min.

Method L

Column: YMC-Pack Jsphere H80, 4 μm, 2.1×33 mm; temperature: roomtemperature; eluent A: water+0.05% TFA; flow rate: 1 ml/min; eluent B:methanol+0.05% TFA; gradient: 2% of B for 1 min, then to 95% of B in 4min, then 95% of B for 1.25 min.

Method M

Column: Acquit/BEH C18, 1.7 μm, 2.1×50 mm; temperature: 40° C.; eluentA: water+0.05% FA; eluent B: ACN+0.035% FA; flow rate: 1.0 ml/min;gradient: from 2% of B to 100% of B in 1.6 min, then 100% of B for 0.5min, then to 2% of B in 0.4 min, then 2% of B for 0.5 min.

Method N

Column: Waters UPLC BEH C18, 1.7 μm, 2.1×50 mm; temperature: 55° C.;eluent A: water+0.05% FA; eluent B: ACN+0.035% FA; flow rate: 0.9ml/min; gradient: from 5% of B to 95% of B in 1.1 min, then 95% of B for0.6 min, then to 5% of B in 0.2 min; then 5% of B for 0.1 min.

Method O

Column: Waters BEH Shield RP18, 1.7 μm, 2,1×50 mm; temperature: 50° C.;eluent A: water+0.1% of FA; eluent B: ACN+0.1% of FA; flow rate: 0.8ml/min; gradient: from 5% of B to 6% of B in 0.05 min, then to 100% of Bin 2.45 min.

EXEMPLARY SYNTHESIS EXAMPLES Example A(E)-1-(2,5-Dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone and2-(5-fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one

2,5-Dihydroxy-acetophenone (3.4 g, 22.4 mmol),5-fluoro-pyridine-3-carbaldehyde (3.1 g, 24.6 mmol, 1.1 eq) and ammoniumacetate (2.2 g, 29.1 mmol, 1.3 eq) were suspended in acetic acid (100%,70 ml) and heated to reflux for 8 h. The solution was allowed to reachroom temperature. The volume of the resulting suspension was reduced tohalf of the volume under reduced pressure. The mixture was poured on icewater and neutralized with caution using sodium carbonate. The aqueouslayer was washed with ethyl acetate and the remaining precipitatefiltered. Solid(E)-1-(2,5-dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g,42%) was obtained as a brownish solid and used in the cyclizationreaction without further purification. The remaining aqueous solutionwas extracted with ethyl acetate and the combined organic layers driedwith sodium sulfate, filtered, the solvent removed under reducedpressure and the resulting solid digested with few dichloromethane.2-(5-Fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one was obtained as abrown solid (2.3 g, 39%) and used in the next step without furtherpurification.

(E)-1-(2,5-Dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g,9.3 mmol) was suspended in methanol (55 ml) and potassium fluoride (2.7g, 46.3 mmol, 5 eq) and diisopropylethylamine (1.2 g, 9.3 mmol, 1 eq)were added. The mixture was heated to reflux for 8 h and afterwardsallowed to reach room temperature. The solvent was removed under reducedpressure. The resulting residue was suspended in water and washed withethyl acetate. The mixture was filtered and the layers separated. Theorganic layer was washed with water, dried with sodium sulfate,filtered, the solvent removed under reduced pressure and the resultingsolid digested with few dichloromethane.2-(5-Fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one was obtained as abrown solid (2.1 g, 88%) and used in the next step without furtherpurification.

According to the described procedure, also the following chromanoneswere synthesized:

-   2-(6-Chloro-pyridin-3-yl)-6-hydroxy-chroman-4-one-   6-Hydroxy-2-(6-methyl-pyridin-3-yl)-chroman-4-one-   6-Hydroxy-3-methyl-2-phenyl-chroman-4-one-   2-(2-Fluoro-3-methoxy-phenyl)-6-hydroxy-chroman-4-one-   6-Hydroxy-3-methyl-2-phenyl-chroman-4-one

Example B (E)-1-(5-Bromo-2-hydroxy-phenyl)-3-o-tolyl-propenone and6-bromo-2-o-tolyl-chroman-4-one

To a solution of o-tolylaldehyde (4.1 g, 33.7 mmol, 1.1 eq) and5-bromo-2-hydroxy-acetophenone (6.9 g, 32.1 mmol) at room temperature inethanol (100 ml) powdered potassium hydroxide (5.2 g, 93 mmol, 5 eq) wasadded and the suspension was stirred at 50° C. for 3 h while a redsolution formed. The solution was allowed to reach room temperature andpoured on ice. The aqueous mixture was adjusted to pH<7 using aqueoushydrochloric acid. The resulting yellow suspension was stirred till ayellow solid formed, and the precipitate filtered, washed with water anddried. The yellow (E)-1-(5-bromo-2-hydroxy-phenyl)-3-o-tolyl-propenone(9.6 g, 94%) was used in the cyclization reaction without furtherpurification.

To a solution of (E)-1-(5-bromo-2-hydroxy-phenyl)-3-o-tolyl-propenone(9.6 g, 30.3 mmol) in ethanol (130 ml) concentrated aqueous hydrochloricacid was added (1.5 ml). The solution was heated to reflux for 5 h.Afterwards the solution was cooled to room temperature and the solventswas removed under reduced pressure. The resulting red6-bromo-2-o-tolyl-chroman-4-one (9.5 g, 100%) was used in the next stepwithout further purification.

According to the described procedure, also the following chromanoneswere synthesized:

-   2-(3-Fluoro-phenyl)-6-hydroxy-chroman-4-one-   6-Bromo-2-(3-isopropoxy-phenyl)-chroman-4-one-   6-Bromo-2-(2-ethyl-phenyl)-chroman-4-one-   6-Hydroxy-2-thiophen-3-yl-chroman-4-one-   2-(2,5-Difluoro-phenyl)-6-hydroxy-chroman-4-one-   6-Bromo-2-(2,6-dimethyl-phenyl)-chroman-4-one-   6-Hydroxy-2-(4-methanesulfonyl-phenyl)-chroman-4-one-   6-Bromo-2-(5-fluoro-2-methyl-phenyl)-chroman-4-one-   6-Hydroxy-2-pyridin-3-yl-chroman-4-one

Example C 6-Bromo-2-o-tolyl-chroman-4-ol and 6-bromo-2-o-tolyl-chroman

To a solution of 6-bromo-2-o-tolyl-chroman-4-one (11.0 g, 34.7 mmol) intetrahydrofuran (100 ml) at room temperature a solution of boranetetrahydrofuran adduct (1M in tetrahydrofuran, 86.7 ml, 2.5 eq) wasadded dropwise. The solution was heated to reflux for 1 h, cooled toroom temperature and added with caution to a mixture of ice water and 1Naqueous hydrochloric acid. The aqueous layer was extracted withdichloromethane, and the combined organic layers washed with water,dried with sodium sulfate and filtered and the solvent removed underreduced pressure. 6-Bromo-2-o-tolyl-chroman-4-ol was obtained as ayellow oil (11.1 g, 100%) and used in the reduction to the chromanwithout further purification.

To a solution of 6-bromo-2-o-tolyl-chroman-4-ol (11.9 g, 37.3 mmol) indichloromethane (130 ml) at 0° C. triethylsilane (29.6 g, 255 mmol, 6.8eq) and trifluoroacetic acid (75 ml, 27 eq) were added. The solution wasstirred at room temperature for 2.5 h. The solvent was removed underreduced pressure and the residue separated between water and ethylacetate. The aqueous layer was extracted with ethyl acetate and thecombined organic layers washed with water and saturated aqueous solutionof sodium hydrogencarbonate, dried with sodium sulfate and filtered, andthe solvent removed under reduced pressure. The crude product waspurified by column chromatography (silica gel; ethyl acetate/heptanegradient). 6-Bromo-2-o-tolyl-chroman was obtained as a pale yellow oil(7.10 g, 63%).

According to the described procedure, also the following chromanderivatives were synthesized:

-   2-(3-Fluoro-phenyl)-chroman-6-ol-   6-Bromo-2-(3-isopropoxy-phenyl)-chroman-   6-Bromo-2-(2-ethyl-phenyl)-chroman-   2-(6-Methyl-pyridin-3-yl)-chroman-6-ol-   2-(2,5-Difluoro-phenyl)-chroman-6-ol-   6-Bromo-2-(2,6-dimethyl-phenyl)-chroman-   6-Bromo-2-(4-methanesulfonyl-phenyl)-chroman-   6-Bromo-2-(5-fluoro-2-methyl-phenyl)-chroman-   2-(6-Chloro-pyridin-3-yl)-chroman-6-ol-   2-Pyridin-3-yl-chroman-6-ol-   2-Thiophen-3-yl-chroman-6-ol-   2-(5-Fluoro-pyridin-3-yl)-chroman-6-ol-   7-Methyl-2-o-tolyl-chroman-6-ol-   2-(2-Fluoro-3-methoxy-phenyl)-chroman-6-ol-   3-Methyl-2-phenyl-chroman-6-ol

Example D (S)-6-Bromo-2-o-tolyl-chroman

a) 3-(5-Bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-one

Sodium hydride (60% in oil, 2.1 g, 52 mmol) and methyl3-oxo-3-o-tolylpropanoate (10 g, 52 mmol) were suspended intetrahydrofuran and 4-bromo-2-(bromomethyl)-1-fluoro-benzene (15.3 g, 57mmol) was added. After complete conversion, the mixture was quenchedwith ice and a saturated solution of ammonium chloride and extractedwith n-heptane. The combined organic layers were washed once with asaturated solution of ammonium chloride, water and brine. The organiclayer was dried over magnesium sulfate and evaporated to dryness. Theobtained yellow oil was dissolved in 25 ml of acetic acid, 25 ml ofconcentrated hydrochloric acid and 20 ml of 1,4-dioxane and heated underreflux for 4 h until LC/MS showed consumption of the starting material.50 ml of water and 100 ml of tert-butyl methyl ether were added and theproduct was extracted. The combined organic layers were washed once withsaturated solution of ammonium chloride, water and brine. The organiclayer was dried over magnesium sulfate and evaporated to dryness. Theresidue was purified by column chromatography (silica gel, heptane/ethylacetate gradient) to give 11.2 g of3-(5-bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-one as a colorless oil.

b) (S)-3-(5-Bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-ol

1 3-(5-Bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-one (14 g, 43.6 mmol)was diluted with 20 ml of dry tetrahydrofuran and added dropwise to asolution of (−)-B-chloro-diisopinocampheyl-borane ((−)-DipCl, 27.96 g,87.2 mmol) in 100 ml of dry tetrahydrofuran while maintaining thetemperature between −30 and −25° C. After 6 h, LC/MS showed completeconversion of the starting material. The cold mixture was quenched with10 ml of methanol and 10 g of sodium hydrogencarbonate and allowed tocome to room temperature. The solvents were removed in vacuum and theobtained yellow oil was dissolved in 200 ml of ethyl acetate and asaturated solution of ammonium chloride. The phases were separated andthe organic layer was washed once with 50 ml of brine, dried overmagnesium sulfate and evaporates to give 45 g of a yellow oil. This oilwas purified by column chromatography (silica gel, heptane/ethyl acetategradient) to give 11.2 g of(S)-3-(5-bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-ol as a colorlessoil.

Ratio of enantiomers (HPLC; column: Chiralcel OJ-H, 250×4.6 mm; eluentheptane/ethyl acetate/methanol 20:1:1); (S):(R)=99.4:0.6

c) (S)-6-Bromo-2-o-tolyl-chroman

3-(5-Bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-O| (10.5 g) was dissolvedin 10 ml of dry N-methylpyrrolidin-2-one, and the solution was addeddropwise to a suspension of sodium hydride (60% in oil, 1.56 g, 39 mmol)in 20 ml of dry N-methylpyrrolidin-2-one at 60° C. After completeaddition the mixture was stirred at 60° C. to reach complete consumptionof the starting material after 12 h. Then the mixture was quenched onice and a saturated solution of ammonium chloride and extracted withn-heptane. The combined organic layers were washed once with a saturatedsolution of ammonium chloride, water and brine. The organic layer wasdried over magnesium sulfate and evaporated to give 12 g of a clear oil.This oil was purified by column chromatography (silica gel,heptane/ethyl acetate gradient) to give 7.7 g of(S)-6-bromo-2-o-tolyl-chroman as a colorless oil.

Example E 2-o-Tolyl-chroman-6-ol

To a solution of 6-bromo-2-o-tolyl-chroman (1 g, 3.3 mmol) intetrahydrofuran (3 ml) at −78° C. n-butyllithium (2.2 M in cyclohexan,1.8 ml, 1.2 eq) was slowly added and the mixture kept at −78° C. for 30min. Triisopropyl borate (1.9 g, 2.3 ml, 9.9 mmol, 3 eq) was added andstirring was continued at the same temperature for 1 h. The coldsolution was poured in a solution of ethanol (1.1 ml), water (3.0 ml)and aqueous sodium hydroxide (8 M, 1.6 ml). To this solution hydrogenperoxide (aqueous 35%, 0.9 ml, 3.1 eq) was slowly added while thetemperature was kept <30° C. Stirring at room temperature was continuedfor 15 min, the suspension was cooled to 0° C. and adjusted to pH<7using aqueous hydrochloric acid. To the resulting solution a saturatedaqueous solution of sodium sulfite (4 ml) was added and the aqueouslayer extracted with ethyl acetate. The combined organic layers weredried with sodium sulfate and filtered, and the solvent removed underreduced pressure. The crude product was purified by columnchromatography (silica gel; ethyl acetate/heptane gradient).2-o-Tolyl-chroman-6-ol was obtained as a pale yellow solid (480 mg,60%).

According to the described procedure, also the following chromanols weresynthesized:

-   2-(3-Isopropoxy-phenyl)-chroman-6-ol-   2-(2-Ethyl-phenyl)-chroman-6-o|-   (S)-2-o-Tolyl-chroman-6-ol-   2-(4-Methanesulfonyl-phenyl)-chroman-6-o|-   2-(5-Fluoro-2-methyl-phenyl)-chroman-6-o|-   2-(2,6-Dimethyl-phenyl)-chroman-6-o|

Example F 2-Pyrazin-2-yl-chroman-6-ol

a) 6-Methoxy-chroman-2-one

To a solution of 5-methoxy-indan-1-one (4.2 g, 25.9 mmol) in 240 ml ofdichloromethane cooled in an ice bath was added sodium hydrogencarbonate(4.35 g, 51.8 mmol). 3-Chloro-perbenzoic acid (11.61 g, 51.8 mmol) wasadded portionwise, and the reaction mixture was stirred at 0° C. for 2 hand at room temperature overnight. The precipitate was filtered off andwashed with dichloromethane. The filtrate was washed with saturatedsolution of sodium hydrogencarbonate and dried with sodium sulfate.After evaporation of the solvent, 6-methoxy-chroman-2-one (3.68 g, 80%)was obtained as an orange oil which was used without furtherpurification.

b) 6-Methoxy-chroman-2-ol

A solution of 6-methoxy-chroman-2-one (3.66 g, 20.53 mmol) in 300 ml ofdichloromethane was cooled to −70° C., and a solution ofdiisobutylaluminium hydride (40 ml of a 1M solution in toluene, 40 mmol)was added dropwise. The solution was stirred at −70° C. for 2 h, andthen ethyl acetate (10 ml) was added. After stirring for 15 min, 200 mlof a saturated solution of Rochelle salt was added dropwise, and themixture was warmed to room temperature. 200 ml of ethyl acetate wereadded, and the mixture was stirred vigorously for 2 h and then decanted.The organic layer was washed with water and brine and dried with sodiumsulfate, and the solvent removed under reduced pressure. The crudeproduct was purified by chromatography on silica gel (ethyl acetate incyclohexane) to afford 2.90 g of white crystals (78%).

c) 2-(3-Hydroxy-3-pyrazin-2-yl-propyl)-4-methoxy-phenol

A solution of 2,2,6,6-tetramethyl-piperidine (8.5 ml, 50.4 mmol) in 200ml of anhydrous tetrahydrofuran was cooled to −30° C., n-butyllithium(20 ml of a 2.5 M solution in hexane, 50 mmol) was added dropwise, andthe mixture stirred for 30 min at 0° C. After cooling at −70° C., asolution of pyrazine (4.0 g, 49.9 mmol) in 50 ml of anhydroustetrahydrofuran was added dropwise. After 10 min at −70° C.,6-methoxy-chroman-2-ol (1.8 g, 10.0 mmol) was added and stirring wascontinued at −70° C. for 1.5 h. The reaction mixture was quenched with20 ml of water and hydrochloric acid added until pH 5-6 was reached.After extraction with ethyl acetate, the organic layer was washed withwater and brine, dried with sodium sulfate and concentrated. Theobtained crude orange oil (960 mg) was used without furtherpurification.

d) 2-(6-Methoxy-chroman-2-yl)-pyrazine

Diethyl azodicarboxylate (0.87 ml, 5.53 mmol) was added dropwise at roomtemperature to a mixture of2-(3-hydroxy-3-pyrazin-2-yl-propyl)-4-methoxy-phenol (960 mg, 3.69 mmol)and triphenylphosphine (1.45 g, 5.53 mmol) in 20 ml of tetrahydrofuran.After stirring at 20° C. for 1 h, the reaction mixture was concentratedand purified by chromatography on silica gel (ethyl acetate incyclohexane). 2-(6-Methoxy-chroman-2-yl)-pyrazine was obtained as whitecrystals (665 mg, 74%).

e) 2-Pyrazin-2-yl-chroman-6-ol

A solution of 2-(6-methoxy-chroman-2-yl)-pyrazine (663 mg, 2.74 mmol) in50 ml of anhydrous dichloromethane was cooled to −10° C., and a solutionof boron tribromide (9.6 ml of 1M solution in dichloromethane, 9.6 mmol)was added dropwise. After stirring at 0° C. for 1 h, 1 ml of borontribromide solution was added and the reaction mixture was stirred at 0°C. for 1.5 h. The reaction mixture was quenched by slow addition ofwater, and after 10 min neutralized by addition of a sodiumhydrogencarbonate solution. After decantation and extraction withdichloromethane, the organic layer was dried over sodium sulfate andconcentrated in vacuo. After chromatography on silica gel (methanol indichloromethane), 2-pyrazin-2-yl-chroman-6-ol was obtained as a yellowpowder (625 mg, 100%).

Example G 2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acidmethyl ester

A suspension of 2-o-Tolyl-chroman-6-ol (2.5 g, 10.4 mmol), methyl2-chloro-thiazole-5-carboxylate (1.9 g, 10.6 mmol, 1.02 eq) andpotassium carbonate (1.9 g, 1.3 eq) in dimethylformamide (30 ml) wasstirred at 50° C. for 10 h. The suspension was cooled to roomtemperature and diluted with water. The aqueous layer was extracted withethyl acetate and the combined organic layers washed with water, driedwith sodium sulfate and filtered, and the solvent was removed underreduced pressure. The crude product was purified by columnchromatography (silica gel; ethyl acetate/heptane gradient). The productwas obtained as a pale yellow solid (3.87 g, 98%).

According to the described procedure, also the following2-(chroman-6-yloxy)-thiazole derivatives were synthesized:

-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester-   4-Chloro-2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    methyl ester-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carbonitrile-   4-Methyl-2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    methyl ester-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carbaldehyde-   2-(2-Phenyl-chroman-6-yloxy)-4-trifluoromethyl-thiazole-5-carboxylic    acid methyl ester-   2-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid    methyl ester-   2-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5-carbonitrile-   2-[2-(4-Methanesulfonyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid methyl ester-   4-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    methyl ester-   2-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl    ester-   2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid methyl ester-   2-[2-(2,5-Difluoro-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid methyl ester-   2-[2-(5-Fluoro-pyridin-3-yl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid methyl ester-   2-[2-(2-Ethyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid    methyl ester-   2-(2-Thiophen-3-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid    methyl ester-   2-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid methyl ester-   2-[2-(6-Chloro-pyridin-3-yl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid methyl ester-   2-(2-Pyrazin-2-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl    ester-   2-[2-(6-Methyl-pyridin-3-yl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid methyl ester-   2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carbonitrile-   2-[2-(3-Isopropoxy-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid methyl ester-   2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-4-carboxylic acid methyl    ester-   2-((S)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl    ester-   2-[2-(2-Fluoro-3-methoxy-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid methyl ester-   2-(7-Methyl-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    methyl ester-   2-(3-Methyl-2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid    methyl ester

Example H 2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid

To a solution of 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylicacid methyl ester (300 mg, 0.8 mmol) in tetrahydrofuran (5.5 ml) andmethanol (1.0 ml) at room temperature a solution of lithium hydroxide(18.9 mg, 1.0 eq) in water (1.0 ml) was added and the mixture stirredfor 3 h. The solvent was removed under reduced pressure and theresulting residue dissolved in water and lyophilized. The obtained white2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid lithium salt(100% yield) was used in the formation of2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid amides withoutfurther purification. For the preparation of the free acid, the crudelithium salt was dissolved in water and the resulting solution acidifiedwith aqueous hydrochloric acid. The resulting suspension was filteredand the precipitate washed with water. The obtained2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid was dried underreduced pressure. It can be used in the next step without furtherpurification as described for the lithium salt.

According to the described procedure, also the following2-(chroman-6-yloxy)-thiazolecarboxylic acids in the form of the freeacid or its lithium salt were synthesized:

-   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid-   4-Chloro-2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid-   4-Methyl-2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid-   2-(2-Phenyl-chroman-6-yloxy)-4-trifluoromethyl-thiazole-5-carboxylic    acid-   2-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid-   2-[2-(4-Methanesulfonyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid-   4-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid-   2-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid-   2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid-   2-[2-(2,5-Difluoro-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid    2-[2-(5-Fluoro-pyridin-3-yl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid-   2-[2-(2-Ethyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid-   2-(2-Thiophen-3-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid-   2-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid-   2-[2-(6-Chloro-pyridin-3-yl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid-   2-(2-Pyrazin-2-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid-   2-[2-(3-Isopropoxy-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid-   2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-4-carboxylic acid-   2-((S)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid-   2-[2-(2-Fluoro-3-methoxy-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic    acid-   2-(7-Methyl-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid-   2-(3-Methyl-2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid

Example J 2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(2-hydroxy-ethyl)-amide

To a solution of 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylicacid lithium salt (100 mg, 0.27 mmol) in dimethylformamide (2 ml)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.38mmol, 1.4 eq), 1-hydroxy-benzotriazole (51 mg, 0.38 mmol, 1.4 eq) andN-methylmorpholine (68 mg, 0.67 mmol, 2.5 eq) were added and the mixturewas stirred at room temperature for 15 min. Ethanolamine (25 mg, 0.40mmol, 1.5 eq) was added and stirring was continued for 16 h. The mixturewas diluted with water and the aqueous layer extracted with ethylacetate. The combined organic layers were washed with a diluted aqueoussolution of sodium carbonate and brine, dried over sodium sulfate andfiltered, and the solvent was removed under reduced pressure. The crudeproduct was purified by column chromatography (silica gel, ethylacetate/methanol gradient). The desired compound was obtained as a whitepowder (43 mg, 39%).

Example K [2-(2-o-Tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine

To a solution of 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonitrile(2.3 g, 6.6 mmol) in tetrahydrofuran (100 ml) an aqueous suspension ofRaney nickel (approximately 500 mg) was added and the resultingsuspension was vigorously stirred under an hydrogen atmosphere(atmospheric pressure) for 1 h (TLC control) at 45° C. The suspensionwas filtered through a celite plug and the filter cake washed with ethylacetate. The organic layer was dried over sodium sulfate and filtered,and the solvent was removed under reduced pressure. The crude productwas purified by column chromatography (silica gel, ethylacetate/methanol gradient).[2-(2-o-Tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine was obtained aspale yellow oil (834 mg, 36%).

Example L Isoxazole-5-carboxylic acid[2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide

To a solution of [2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine(150 mg, 0.43 mmol) in DMF (2 ml),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (114 mg,0.60 mmol, 1.4 eq), 1-hydroxy-benzotriazole (81 mg, 0.60 mmol, 1.4 eq)and N-methylmorpholine (107 mg, 1.07 mmol, 2.5 eq) andisoxazole-5-carboxylic acid (72 mg, 0.64 mmol, 1.5 eq) were added. Themixture was stirred for 16 h, then diluted with water, and the aqueouslayer was extracted with ethyl acetate. The combined organic layers werewashed with a diluted aqueous solution of sodium carbonate and brine,dried over sodium sulfate and filtered, and the solvent was removedunder reduced pressure. The crude product was purified by columnchromatography (silica gel, ethyl acetate/methanol gradient).Isoxazole-5-carboxylic acid[2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide (112 mg, 59%)was obtained as a white solid.

Example M[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-pyridin-4-ylmethyl-amine

To a suspension of 2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carbaldehyde(54 mg, 0.13 mmol) and pyridin-4-yl-methylamine (17 mg, 0.16 mmol, 1.2eq) in tetrahydrofuran (3 ml) and acetic acid (0.5 ml) at 0° C. sodiumcyanoborohydride (polymer bond, 2.19 mM/g, 137 mg, 0.30 mmol, 2.3 eq)was added and the mixture stirred at 40° C. for 16 h. The reactionmixture was filtered, the volatile components removed under reducedpressure and the remaining residue purified by reversed phase HPLC(water/acetonitrile gradient (+0.1% trifluoroacetic acid)) to give 30 mg(42%) of[2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-pyridin-4-ylmethyl-aminein the form of its salt with trifluoroacetic acid.

Example N 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid[2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide

33 mg of 1,3,5-trimethyl-1H-pyrazole-4-sulfonic acid chloride (0.16mmol, 1.2 eq) were weighted into a reaction tube and dissolved in drytetrahydrofuran (1 ml). 44 mg of[2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine (0.13 mmol) indry tetrahydrofuran (3 ml) and 30 mg triethylamine (0.3 mmol, 2.3 eq)were added, the tube was flushed with argon, closed with a screw cap,and shaken over night at 40° C. 0.008 ml of tris-(2-aminoethyl)amine in0.5 ml tetrahydrofuran were added, the mixture was shaken for 2 h atroom temperature and then evaporated. The residue was dissolved in 2 mlof a mixture of dimethylformamide/trifluoroacetic acid (19:1), filtered,and submitted to preparative reversed phase HPLC purification(water/acetonitrile gradient (+0.1% trifluoroacetic acid)).1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid[2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide was obtained asa white solid (42 mg, 63%).

Example O Phosphoric acidmono-(2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethyl)esterdisodium salt

a) Phosphoric acid dibenzyl ester2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethylester

To a suspension of2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(2-hydroxy-ethyl)-amide (1 g, 2.44 mmol) and tetrazole (222 mg, 3.17mmol, 1.3 eq) in dichloromethane (14 ml) and acetonitrile (14 ml) at 0°C., dibenzyl-N,N-diisopropylphosphoramidite (1.01 g, 2.92 mmol, 1.2 eq)was added and the mixture stirred at 0° C. for 70 min. To the resultingsolution 3-chloro-perbenzoic acid (65%, 776 mg, 2.92 mmol, 1.2 eq) wasadded in one portion and vigorous stirring at 0° C. was continued for 10min. The mixture was diluted with dichloromethane and the organic layerwashed with a saturated aqueous solution of sodium hydrogencarbonate andsubsequently with a saturated aqueous solution of ammonium chloride. Thecombined organic layers were dried over sodium sulfate and filtered, andthe solvent removed under reduced pressure. The crude product waspurified by column chromatography (silica gel, ethyl acetate).Phosphoric acid dibenzyl ester2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethylester was obtained as a colorless oil (1.30 g, 80%).

b) Phosphoric acidmono-(2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethyl)esterdisodium salt

Phosphoric acid dibenzyl ester2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethylester (1.3 g, 1.95 mmol) was dissolved in methanol (40 ml) and palladiumon charcoal was added (10% Pd, 54% water, 1.3 g). The suspension wasvigorously stirred under a hydrogen atmosphere. The mixture was filteredand the filter cake rinsed with methanol. The filtrate was evaporatedunder reduced pressure and the resulting crude product submitted topreparative reversed phase HPLC purification (water/acetonitrilegradient (+0.1% trifluoroacetic acid)). The obtained phosphoric acidmono-(2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethyl)esterwas suspended in water and converted into the disodium salt by additionof 2 equivalents of an aqueous 0.5 N sodium hydroxide solution. Theobtained aqueous solution was lyophilized to yield phosphoric acidmono-(2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethyl)esterdisodium salt as a white solid (460 mg, 44%).

In analogy to the procedures described above in the synthesis examples,the example compounds of the formula I listed in Table 1 were prepared.In Table 1, “Ex. no.” means the number of the example compound; “LC/MS”means the LC/MS method described above which was used in the HPLC and MScharacterization of the example compound; “MS” means the mass number (inamu) of the peak of the molecular ion or a related ion such as M+1 inthe mass spectrum, in the case of a salt of the parent compound, i.e.the free acid or base; “Rt” means the HPLC retention time (in minutes);and “NCX1rv IC₅₀” means the IC₅₀ value for inhibition of NCX1 in reversemode determined in the assay for inhibition of Ca²⁺influx into cells(reverse mode) described below (in μM (micromol/liter)).

TABLE 1 Example compounds of the formula I Ex. LC/ NCX1rv no. Compoundname MS MS Rt IC₅₀ 1 2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylicA 461 4.97 0.3 acid (1-ethyl-1H-pyrazol-4-ylmethyl)-amide 22-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic B 474.21 2.15 0.3acid (6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3- ylmethyl)-amide 32-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic C 461.29 5.02 0.4acid (2-ethyl-2H-pyrazol-3-ylmethyl)-amide 42-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic B 444.17 2.11 0.3acid (pyridin-4-ylmethyl)-amide 52-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic B 447.17 2.4 0.4 acid(2-methyl-2H-pyrazol-3-ylmethyl)-amide 62-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic C 458.27 4.02 0.4acid (1-pyridin-4-yl-ethyl)-amide 72-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic B 478.14 2.29 0.3acid [2-(4-methyl-thiazol-5-yl)-ethyl]-amide 82-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic C 475.23 4.9 0.8 acid[1-(1,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-amide 92-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic B 458.18 2.13 0.8acid (2-methyl-pyridin-4-ylmethyl)-amide 102-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic B 474.14 2.38 0.6acid (2-methoxy-pyridin-4-ylmethyl)-amide 112-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic D 459 1.13 0.4 acid(2-amino-pyridin-4-ylmethyl)-amide 122-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5- D 477 1.14 0.2carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide 132-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5- D 476 1.14 0.3carboxylic acid (1-pyridin-4-yl-ethyl)-amide hydrochloride 142-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic C 461.33 4.75 0.3acid (1,5-dimethyl-1H-pyrazol-4-ylmethyl)-amide 15N-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- D 444 1.16 0.1ylmethyl]-nicotinamide hydrochloride 16N-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- D 458 1.08 0.1ylmethyl]-2-pyridin-3-yl-acetamide hydrochloride 172-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5- D 502 1.2 0.2carboxylic acid ([1,2,4]triazolo[4,3-a]pyridin-3- ylmethyl)-amidehydrochloride 18 2-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5- D462 1.13 0.2 carboxylic acid (pyridin-4-ylmethyl)-amide hydrochloride 19N-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- D 458 1.09 0.1ylmethyl]-2-pyridin-2-yl-acetamide hydrochloride 202-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5- D 492 1.15 0.2carboxylic acid (6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-ylmethyl)-amide hydrochloride 212-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic C 459.69 4.64 0.1acid (2-methyl-pyrimidin-4-ylmethyl)-amide 222-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic E 502.15 1.86 0.4acid [(S)-1-(6-methoxy-pyridin-3-yl)-propyl]-amide 232-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic E 475.17 1.73 0.8acid [1-(1,3-dimethyl-1H-pyrazol-4-yl)-ethyl]-amide 242-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic E 434.12 1.77 0.1acid (isoxazol-5-ylmethyl)-amide 252-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic E 513.17 1.6 0.4 acid(2-pyrrolidin-1-yl-pyridin-4-ylmethyl)-amide 262-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic E 527.21 1.01 0.3acid methyl-(2-pyrrolidin-1-yl-pyridin-4-ylmethyl)- amide 272-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic E 502.17 1.86 0.3acid [(R)-1-(6-methoxy-pyridin-3-yl)-propyl]-amide 282-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic E 529.19 1.57 0.2acid (2-morpholin-4-yl-pyridin-4-ylmethyl)-amide 292-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic E 487.17 1.57 0.1acid (2-dimethylamino-pyridin-4-ylmethyl)-amide 302-(2-Phenyl-chroman-6-yloxy)-4-trifluoromethyl- F 512 1.21 0.3thiazole-5-carboxylic acid (pyridin-4-ylmethyl)- amide hydrochloride 312-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic G 475.31 3.15 1.0acid [1-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-amide 322-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic G 445.27 3.4 0.6 acid(pyrimidin-4-ylmethyl)-amide 332-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic G 473.26 3.54 0.2acid (4,6-dimethyl-pyrimidin-2-ylmethyl)-amide 342-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic G 476.27 3.82 0.2acid [2-(3,5-dimethyl-isoxazol-4-yl)-ethyl]-amide 352-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic G 484.27 3.27 0.6acid ([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-amide 362-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- D 444 1.12 0.1 carboxylicacid (pyridin-4-ylmethyl)-amide 372-((R)-2-Phenyl-chroman-6-yloxy)-thiazole-5- C 444.35 3.89 0.2carboxylic acid (pyridin-4-ylmethyl)-amide 382-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic G 490.26 3.95 0.3acid [3-(3,5-dimethyl-isoxazol-4-yl)-propyl]-amide 392-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic G 478.21 3.89 0.3acid (2-chloro-pyridin-4-ylmethyl)-amide 402-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic H 478.2 1.29 0.4 acid(3-chloro-pyridin-4-ylmethyl)-amide 412-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic G 483.25 3.05 5.0acid (imidazo[1,2-a]pyridin-2-ylmethyl)-amide 422-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic H 460.19 1.18 0.2acid (2-hydroxy-pyridin-4-ylmethyl)-amide 43N-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- D 458 1.08 0.3ylmethyl]-2-pyridin-4-yl-acetamide hydrochloride 44N-{2-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazol- D 462 1.17 0.25-ylmethyl}-nicotinamide hydrochloride 45N-{2-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazol- D 476 1.1 0.15-ylmethyl}-2-pyridin-3-yl-acetamide hydrochloride 46N-{2-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazol- D 476 1.1 0.25-ylmethyl}-2-pyridin-4-yl-acetamide hydrochloride 47Pyridine-3-sulfonic acid [2-(2-phenyl-chroman-6- D 480 1.31 0.1yloxy)-thiazol-5-ylmethyl]-amide hydrochloride 48 Isoxazole-5-carboxylicacid [2-(2-phenyl-chroman- C 434.67 5 0.16-yloxy)-thiazol-5-ylmethyl]-amide 492-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5- F 452 4.62 0.1carboxylic acid (isoxazol-5-ylmethyl)-amide 501-Methyl-1H-imidazole-4-sulfonic acid [2-(2-phenyl- D 1.3 483 0.2chroman-6-yloxy)-thiazol-5-ylmethyl]-amide hydrochloride 512-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5- D 479 1.28 0.2carboxylic acid (1,5-dimethyl-1H-pyrazol-4- ylmethyl)-amide 522-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic L 504.13 4.75 0.4acid [(S)-1-(4-cyclopropyl-thiazol-2-yl)-ethyl]-amide 532-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic L 506.13 4.77 0.7acid [(S)-1-(4-isopropyl-thiazol-2-yl)-ethyl]-amide 542-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic L 464.1 4.47 0.2 acid((S)-1-thiazol-2-yl-ethyl)-amide 552-(5-Chloro-2-phenyl-chroman-6-yloxy)-thiazole-5- I 478 1.31 1.2carboxylic acid (pyridin-4-ylmethyl)-amide hydrochloride 562-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5- D 477 1.28 0.2carboxylic acid (2-methyl-pyrimidin-4-ylmethyl)- amide hydrochloride 57C-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-yl]- C 0.1 methylamine 582-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5- I 435 0.97 0.6 carboxylicacid (isoxazol-5-ylmethyl)-amide hydrochloride 594-Methyl-2-(2-phenyl-chroman-6-yloxy)-thiazole-5- C 458.31 3.99 0.1carboxylic acid (pyridin-4-ylmethyl)-amide hydrochloride 602-(2-Thiophen-3-yl-chroman-6-yloxy)-thiazole-5- I 450 1.15 0.1carboxylic acid (pyridin-4-ylmethyl)-amide hydrochloride 612-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic D 458 1.11 0.2 acid(2-pyridin-4-yl-ethyl)-amide hydrochloride 622-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- D 461 1.29 0.3 carboxylicacid (1,5-dimethyl-1H-pyrazol-4- ylmethyl)-amide 632-((R)-2-Phenyl-chroman-6-yloxy)-thiazole-5- D 461 1.29 0.6 carboxylicacid (1,5-dimethyl-1H-pyrazol-4- ylmethyl)-amide 646-Methyl-N-[2-(2-phenyl-chroman-6-yloxy)-thiazol- H 458.42 1.27 1.35-ylmethyl]-nicotinamide 65 3,5-Dimethyl-isoxazole-4-carboxylic acid[2-(2- H 462.41 1.33 0.2phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 662,5-Dimethyl-2H-pyrazole-3-carboxylic acid [2-(2- H 461.44 1.33 0.6phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 671,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid [2-(2- H 475.45 1.29 0.3phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 682-Chloro-N-[2-(2-phenyl-chroman-6-yloxy)-thiazol- H 478.36 1.36 0.85-ylmethyl]-isonicotinamide 69 4-Methyl-oxazole-5-carboxylic acid[2-(2-phenyl- H 448.38 1.31 0.5chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 702-Ethyl-2H-pyrazole-3-carboxylic acid [2-(2-phenyl- H 461.43 1.34 0.3chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 711,5-Dimethyl-1H-pyrazole-4-carboxylic acid [2-(2- H 461.43 1.28 0.7phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 721-Ethyl-1H-pyrazole-4-carboxylic acid [2-(2-phenyl- H 461.42 1.29 0.3chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 732-Methyl-thiazole-4-carboxylic acid [2-(2-phenyl- H 464.35 1.35 0.3chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 742-(3-Methyl-pyrazol-1-yl)-N-[2-(2-phenyl-chroman- H 461.45 1.3 0.36-yloxy)-thiazol-5-ylmethyl]-acetamide 753,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic H 527.12 1.3 9.8acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5- ylmethyl]-amide 762-Methoxy-N-[2-(2-phenyl-chroman-6-yloxy)-thiazol- H 474.41 1.35 5.65-ylmethyl]-isonicotinamide 772-(3,5-Dimethyl-isoxazol-4-yl)-N-[2-(2-phenyl- H 476.42 1.31 0.4chroman-6-yloxy)-thiazol-5-ylmethyl]-acetamide 782,4-Dimethyl-oxazole-5-carboxylic acid [2-(2- H 462.38 1.31 0.3phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 79N-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- H 444.38 1.27 0.2ylmethyl]-isonicotinamide 803-Chloro-N-[2-(2-phenyl-chroman-6-yloxy)-thiazol- H 478.34 1.32 0.25-ylmethyl]-isonicotinamide 813-Fluoro-N-[2-(2-phenyl-chroman-6-yloxy)-thiazol-5- H 462.37 1.32 1.1ylmethyl]-isonicotinamide 822-Methyl-N-[2-(2-phenyl-chroman-6-yloxy)-thiazol- H 458.43 1.26 0.45-ylmethyl]-isonicotinamide 832-Morpholin-4-yl-N-[2-(2-phenyl-chroman-6-yloxy)- H 529.47 1.31 2.1thiazol-5-ylmethyl]-isonicotinamide 84 3-Methyl-isoxazole-5-carboxylicacid [2-(2-phenyl- H 448.36 1.33 0.3chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 852-Amino-N-[2-(2-phenyl-chroman-6-yloxy)-thiazol-5- H 459.4 1.12 10.9ylmethyl]-isonicotinamide 86 2-Methyl-2H-pyrazole-3-carboxylic acid[2-(2- H 447.39 1.32 0.3phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 87Pyrimidine-2-carboxylic acid [2-(2-phenyl-chroman- H 445.39 1.27 0.46-yloxy)-thiazol-5-ylmethyl]-amide 882-Hydroxy-N-[2-(2-phenyl-chroman-6-yloxy)-thiazol- H 460.32 1.23 5.05-ylmethyl]-isonicotinamide 89 Pyrimidine-4-carboxylic acid[2-(2-phenyl-chroman- H 445.4 1.31 0.26-yloxy)-thiazol-5-ylmethyl]-amide 90N-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- H 461.44 1.28 0.6ylmethyl]-3-pyrazol-1-yl-propionamide 912,6-Dimethyl-pyrimidine-4-carboxylic acid [2-(2- H 473.44 1.36 5.3phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 92N-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- H 447.42 1.28 1.1ylmethyl]-2-pyrazol-1-yl-acetamide 93 1-Ethyl-1H-pyrazole-3-carboxylicacid [2-(2-phenyl- H 461.44 1.33 0.5chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 943-(3,5-Dimethyl-isoxazol-4-yl)-N-[2-(2-phenyl- H 490.46 1.31 0.9chroman-6-yloxy)-thiazol-5-ylmethyl]-propionamide 952-(2,5-Dioxo-imidazolidin-1-yl)-N-[2-(2-phenyl- H 479.3 1.19 0.6chroman-6-yloxy)-thiazol-5-ylmethyl]-acetamide 962-[2-(3-Isopropoxy-phenyl)-chroman-6-yloxy]- H 502.48 1.12 0.8thiazole-5-carboxylic acid (pyridin-4-ylmethyl)- amide 972-[2-(3-Isopropoxy-phenyl)-chroman-6-yloxy]- H 534.35 1.39 1.2thiazole-5-carboxylic acid [2-(3,5-dimethyl-isoxazol- 4-yl)-ethyl]-amide98 4-Methyl-2-((S)-2-phenyl-chroman-6-yloxy)- D 458 1.13 0.3thiazole-5-carboxylic acid (pyridin-4-ylmethyl)- amide hydrochloride 99Butyl-methyl-[2-(2-phenyl-chroman-6-yloxy)-thiazol- J 409.34 4.99 0.75-ylmethyl]-amine 100 (2R,6S)-2,6-Dimethyl-4-[2-(2-phenyl-chroman-6- H437.34 1.19 1.0 yloxy)-thiazol-5-ylmethyl]-morpholine 101Isobutyl-[2-(2-phenyl-chroman-6-yloxy)-thiazol-5- H 395.29 1.16 0.4ylmethyl]-amine 102 1-Methyl-4-[2-(2-phenyl-chroman-6-yloxy)-thiazol-5-H 436.3 1.26 0.4 ylmethyl]-piperazin-2-one 103Cyclopropyl-[2-(2-phenyl-chroman-6-yloxy)-thiazol- H 379.26 1.13 0.25-ylmethyl]-amine 104 2-(2-Phenyl-chroman-6-yloxy)-5-pyrrolidin-1- H393.29 1.13 0.4 ylmethyl-thiazole 105[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]- H 423.33 1.19 0.8(1,2,2-trimethyl-propyl)-amine 106(1-Ethyl-propyl)-[2-(2-phenyl-chroman-6-yloxy)- H 409.3 1.17 0.5thiazol-5-ylmethyl]-amine 107[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]- H 421.24 1.39 0.2(2,2,2-trifluoro-ethyl)-amine 1083-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- H 447.37 1.19 1.4ylmethyl]-3-aza-bicyclo[3.2.2]nonane 1094,4-Difluoro-1-[2-(2-phenyl-chroman-6-yloxy)- H 443.28 1.28 0.7thiazol-5-ylmethyl]-piperidine 110Cyclobutyl-[2-(2-phenyl-chroman-6-yloxy)-thiazol-5- H 393.28 1.14 0.2ylmethyl]-amine 111 (3-Methyl-isoxazol-5-yl)-[2-(2-phenyl-chroman-6- H420.26 1.28 0.8 yloxy)-thiazol-5-ylmethyl]-amine 112(1,1-Dimethyl-propyl)-[2-(2-phenyl-chroman-6- H 409.31 1.15 0.3yloxy)-thiazol-5-ylmethyl]-amine 113Isopropyl-[2-(2-phenyl-chroman-6-yloxy)-thiazol-5- H 381.27 1.13 0.3ylmethyl]-amine 114 (2-Methoxy-ethyl)-[2-(2-phenyl-chroman-6-yloxy)- H397.28 1.13 0.2 thiazol-5-ylmethyl]-amine 115(3-Methyl-butyl)-[2-(2-phenyl-chroman-6-yloxy)- H 409.29 1.4 0.6thiazol-5-ylmethyl]-amine 116[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]- H 381.25 1.13 0.2propyl-amine 117 4-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- H 409.261.14 0.3 ylmethyl]-morpholine 118tert-Butyl-[2-(2-phenyl-chroman-6-yloxy)-thiazol-5- H 395.26 1.13 0.4ylmethyl]-amine 119 Dimethyl-[2-(2-phenyl-chroman-6-yloxy)-thiazol-5- H367.23 1.11 0.4 ylmethyl]-amine 120Cyclopropylmethyl-[2-(2-phenyl-chroman-6-yloxy)- H 393.1 1.02 0.3thiazol-5-ylmethyl]-amine 121 7-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-J 419.34 3.76 0.6 ylmethyl]-7-aza-bicyclo[2.2.1]heptane 1221-Methyl-4-[2-(2-phenyl-chroman-6-yloxy)-thiazol-5- H 422.33 1.14 0.8ylmethyl]-piperazine 123 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7- H550.3 1.36 1.1 sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 124 2-Methyl-benzothiazole-6-sulfonic acid[2-(2-phenyl- H 550.24 1.35 0.9chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 1251,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid [2-(2- H 511.29 1.31 9.2phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 1262,4-Dimethyl-thiazole-5-sulfonic acid [2-(2-phenyl- H 514.25 1.34 0.6chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 1272,3-Dimethyl-3H-imidazole-4-sulfonic acid [2-(2- H 497.3 1.22 1.1phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 1282-Methyl-2H-pyrazole-3-sulfonic acid [2-(2-phenyl- H 483.26 1.32 0.3chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 1291-Methyl-1H-pyrazole-4-sulfonic acid [2-(2-phenyl- H 483.24 1.29 0.9chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 1301-Isopropyl-5-methyl-1H-pyrazole-4-sulfonic acid [2- H 525.31 1.35 0.7(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]- amide 1313,5-Dimethyl-1H-pyrazole-4-sulfonic acid [2-(2- H 497.24 1.27 23.8phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 1321-Ethyl-1H-pyrazole-4-sulfonic acid [2-(2-phenyl- H 497.27 1.31 0.3chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 1331,5-Dimethyl-1H-pyrazole-4-sulfonic acid [2-(2- H 497.26 1.3 0.4phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 134[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]- H 430.29 1.1 0.2pyridin-4-ylmethyl-amine 135 (5-Methyl-pyrazin-2-ylmethyl)-[2-(2-phenyl-H 445.32 1.13 0.5 chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 136[2-(3-Methyl-pyrazol-1-yl)-ethyl]-[2-(2-phenyl- H 447.33 1.16 0.5chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 137(1,3-Dimethyl-1H-pyrazol-4-ylmethyl)-[2-(2-phenyl- H 447.33 1.12 0.4chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 138(1,5-Dimethyl-1H-pyrazol-4-ylmethyl)-[2-(2-phenyl- H 447.33 1.12 0.3chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 139(1-Ethyl-3-methyl-1H-pyrazol-4-ylmethyl)-[2-(2- H 461.36 1.13 0.5phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 140(5-Methyl-isoxazol-3-ylmethyl)-[2-(2-phenyl- H 434.3 1.15 0.2chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 141(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-[2-(2-phenyl- H 447.33 1.13 0.4chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 142[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]- H 447.36 1.13 0.3(3-pyrazol-1-yl-propyl)-amine 143(4,6-Dimethyl-pyrimidin-2-ylmethyl)-[2-(2-phenyl- H 459.35 1.15 0.5chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 144(6,7-Dihydro-5H-thiazolo[3,2-a]pyrimidin-3- H 491.33 1.11 0.8ylmethyl)-[2-(2-phenyl-chroman-6-yloxy)-thiazol-5- ylmethyl]-amine 145(2-Morpholin-4-yl-pyridin-3-ylmethyl)-[2-(2-phenyl- J 515.32 3.7 0.9chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 146(2-Methyl-2H-pyrazol-3-ylmethyl)-[2-(2-phenyl- H 433.32 1.12 0.2chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 147(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-[2-(2-phenyl- H 447.35 1.14 0.3chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 148[1-(1,5-Dimethyl-1H-pyrazol-4-yl)-ethyl]-[2-(2- H 461.36 1.12 0.4phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 149[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]- H 433.32 1.14 0.3(2-pyrazol-1-yl-ethyl)-amine 150[2-(3,5-Dimethyl-pyrazol-1-yl)-ethyl]-[2-(2-phenyl- H 461.37 1.17 0.8chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 151[2-(4-Methyl-thiazol-2-yl)-ethyl]-[2-(2-phenyl- H 464.32 1.16 0.4chroman-6-yloxy)-thiazol-5-ylmethy]-amine 152(3,5-Dimethyl-isoxazol-4-ylmethyl)-[2-(2-phenyl- H 448.31 1.14 0.3chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 153[3-(3,5-Dimethyl-isoxazol-4-yl)-propyl]-[2-(2-phenyl- H 476.36 1.15 0.5chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 1544-({[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- H 446.3 1.08 0.3ylmethyl]-amino}-methyl)-pyridin-2-ol 1554-({[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- H 445.31 1.04 0.4ylmethyl]-amino}-methyl)-pyridin-2-ylamine 156[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]- H 470.34 1.15 0.4[1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl-amine 1575-({[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- H 455.3 1.16 0.2ylmethyl]-amino}-methyl)-pyridine-2-carbonitrile 158Imidazo[2,1-b]thiazol-6-ylmethyl-[2-(2-phenyl- H 475.29 1.14 0.3chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 159Isoxazol-5-ylmethyl-[2-(2-phenyl-chroman-6-yloxy)- H 420.28 1.15 0.1thiazol-5-ylmethyl]-amine 160(3-Methyl-isoxazol-5-ylmethyl)-[2-(2-phenyl- H 434.3 1.16 0.2chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 161[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]- H 431.29 1.12 0.3pyrimidin-4-ylmethyl-amine 162(2-Morpholin-4-yl-pyridin-4-ylmethyl)-[2-(2-phenyl- H 515.4 1.13 0.4chroman-6-yloxy)-thiazol-5-ylmethyl]-amine 1631,2-Dimethyl-1H-imidazole-4-sulfonic acid [2-(2- H 497.3 1.26 0.4phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 1642-(3-Methyl-2,5-dioxo-imidazolidin-1-yl)-N-[2-(2- H 493.26 1.25 0.7phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]- acetamide 1652-(2-Oxo-pyrrolidin-1-yl)-N-[2-(2-phenyl-chroman-6- H 464.26 1.25 0.5yloxy)-thiazol-5-ylmethyl]-acetamide 1664-Methyl-2-(2-phenyl-chroman-6-yloxy)-thiazole-5- M 448 1.31 0.3carboxylic acid (isoxazol-5-ylmethyl)-amide 1674-Methyl-2-(2-phenyl-chroman-6-yloxy)-thiazole-5- M 492 1.39 0.5carboxylic acid (2-chloro-pyridin-4-ylmethyl)-amide hydrochloride 1684-Methyl-2-((S)-2-phenyl-chroman-6-yloxy)- C 448.29 5.14 0.2thiazole-5-carboxylic acid (isoxazol-5-ylmethyl)- amide 1694-Methyl-2-((S)-2-phenyl-chroman-6-yloxy)- M 472 1.01 0.3thiazole-5-carboxylic acid (2-pyridin-4-yl-ethyl)- amide hydrochloride170 4-Methyl-2-(2-phenyl-chroman-6-yloxy)-thiazole-5- M 472 1.02 0.3carboxylic acid (2-pyridin-4-yl-ethyl)-amide hydrochloride 1712-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- C 434.27 5.05 0.1carboxylic acid (isoxazol-5-ylmethyl)-amide 1722-((R)-2-Phenyl-chroman-6-yloxy)-thiazole-5- M 434 1.28 0.4 carboxylicacid (isoxazol-5-ylmethyl)-amide 1732-[2-(3-Hydroxy-phenyl)-chroman-6-yloxy]-thiazole- H 492.32 1.22 2.35-carboxylic acid [2-(3,5-dimethyl-isoxazol-4-yl)- ethyl]-amide 1742-[2-(3-Hydroxy-phenyl)-chroman-6-yloxy]-thiazole- H 460.24 1.07 0.85-carboxylic acid (pyridin-4-ylmethyl)-amide hydrochloride 1752-((R)-3-Hydroxy-pyrrolidin-1-yl)-N-[2-(2-phenyl- H 466.16 0.99 0.4chroman-6-yloxy)-thiazol-5-ylmethyl]-acetamide 1762-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic H 490.16 1.26 0.4acid [2-(3,5-dimethyl-isoxazol-4-yl)-ethyl]-amide 1774-Chloro-2-(2-phenyl-chroman-6-yloxy)-thiazole-5- D 0.3 carboxylic acid(pyridin-4-ylmethyl)-amide hydrochloride 1784-Methyl-2-((S)-2-phenyl-chroman-6-yloxy)- D 0.4 thiazole-5-carboxylicacid (2-chloro-pyridin-4- ylmethyl)-amide hydrochloride 1792-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic H 458.07 1.08 0.5acid (pyridin-4-ylmethyl)-amide 180(S)-2-{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole- H 453.26 1.36 0.25-carbonyl]-amino}-propionic acid ethyl ester 181{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 425.22 1.31 0.2carbonyl]-amino}-acetic acid methyl ester 1822-Methyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 453.25 1.35 0.6thiazole-5-carbonyl]-amino}-propionic acid methyl ester 183(S)-3-Methyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 481.34 1.41 1.2thiazole-5-carbonyl]-amino}-pentanoic acid methyl ester 184(R)-2-{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole- H 439.25 1.34 0.45-carbonyl]-amino}-propionic acid methyl ester 185(S)-1-[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 465.11 1.24 0.5carbonyl]-pyrrolidine-2-carboxylic acid methyl ester 186(S)-3-Methyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 481.35 1.42 0.7thiazole-5-carbonyl]-amino}-butyric acid ethyl ester 1871-{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 479.31 1.38 0.6carbonyl]-amino}-cyclopentanecarboxylic acid methyl ester 1881-{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 465.31 1.35 0.6carbonyl]-amino}-cyclopropanecarboxylic acid ethyl ester 189(1R,2S)-2-{[2-((S)-2-Phenyl-chroman-6-yloxy)- H 507.38 1.43 0.6thiazole-5-carbonyl]-amino}-cyclohexanecarboxylic acid ethyl ester 190{Methyl-[2-((S)-2-phenyl-chroman-6-yloxy)-thiazole- H 425.26 1.27 0.95-carbonyl]-amino}-acetic acid 191(S)-2-{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole- H 425.26 1.28 0.65-carbonyl]-amino}-propionic acid 192{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 411.25 1.25 0.5carbonyl]-amino}-acetic acid 1932-Methyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 439.12 1.18 0.6thiazole-5-carbonyl]-amino}-propionic acid 194(R)-2-{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole- H 425.12 1.16 0.75-carbonyl]-amino}-propionic acid 1951-{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 465.12 1.21 0.7carbonyl]amino}-cyclopentanecarboxylic acid 196(S)-3-Methyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 467.17 1.24 0.5thiazole-5-carbonyl]-amino}-pentanoic acid 197(S)-3-Methyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 453.14 1.21 0.6thiazole-5-carbonyl]-amino}-butyric acid 198{4-[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 480.16 1.05 1.3carbonyl]-piperazin-1-yl}-acetic acid 1991-{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 437.1 1.16 1.0carbonyl]-amino}cyclopropanecarboxylic acid 200(1R,2S)-2-{[2-((S)-2-Phenyl-chroman-6-yloxy)- H 479.16 1.23 0.4thiazole-5-carbonyl]-amino}-cyclohexanecarboxylic acid 2012-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 473.26 1.33 0.3carboxylic acid ((S)-2-hydroxy-1-phenyl-ethyl)- amide 2022-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 439.13 1.12 0.2carboxylic acid ((1S,2S)-2-hydroxy-1- hydroxymethyl-propyl)-amide 2032-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 439.28 1.32 0.4carboxylic acid ((S)-1-hydroxymethyl-2-methyl- propyl)-amide 2042-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 397.03 1.14 0.1carboxylic acid (2-hydroxy-ethyl)-amide 205((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-[2-((S)-2- H 437.27 1.3 0.3phenyl-chroman-6-yloxy)-thiazol-5-yl]-methanone 2062-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 451.29 1.32 0.3carboxylic acid (1-cyclopropyl-3-hydroxy-propyl)- amide 2072-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 465.14 1.25 0.5carboxylic acid ((1R,2R)-2-hydroxy- cyclohexylmethyl)-amide 2082-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 453.15 1.24 0.4carboxylic acid ((1S,2S)-1-hydroxymethyl-2-methyl- butyl)-amide 2092-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 453.29 1.35 0.3carboxylic acid ((1R,2R)-1-hydroxymethyl-2-methyl- butyl)-amide 210Isoxazol-5-ylmethyl-[2-((S)-2-phenyl-chroman-6- O 420 1.17 0.1yloxy)-thiazol-5-ylmethyl]-amine 2112-(2-Thiophen-3-yl-chroman-6-yloxy)-thiazole-5- F 484 4.7 0.4 carboxylicacid (2-chloro-pyridin-4-ylmethyl)-amide hydrochloride 2122-(2-Thiophen-3-yl-chroman-6-yloxy)-thiazole-5- F 440 4.45 0.3carboxylic acid (isoxazol-5-ylmethyl)-amide 213(4-Methyl-piperazin-1-yl)-[2-((S)-2-phenyl-chroman- F 436 4.4 0.86-yloxy)-thiazol-5-yl]-methanone hydrochloride 214Morpholin-4-yl-[2-((S)-2-phenyl-chroman-6-yloxy)- F 423 4.57 0.5thiazol-5-yl]-methanone 2152-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic L 492.2 4.7 1.0 acid(2-chloro-pyridin-4-ylmethyl)-amide 2162-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic L 479.29 4.35 0.3acid [2-(2-oxo-imidazolidin-1-yl)-ethyl]-amide 2172-[2-(2,5-Difluoro-phenyl)-chroman-6-yloxy]- O 470 1.83 0.2thiazole-5-carboxylic acid (isoxazol-5-ylmethyl)- amide 2182-Methyl-3-phenyl-2-{[2-((S)-2-phenyl-chroman-6- H 529.09 1.31 2.5yloxy)-thiazole-5-carbonyl]-amino}-propionic acid methyl ester 219(S)-3-Phenyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 529.08 1.31 4.8thiazole-5-carbonyl]-amino}-propionic acid ethyl ester 220(S)-3,3-Dimethyl-2-{[2-((S)-2-phenyl-chroman-6- H 481.13 1.3 0.6yloxy)-thiazole-5-carbonyl]-amino}-butyric acid methyl ester 2211-[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 533.04 1.27 0.3carbonyl]-4-trifluoromethyl-pyrrolidine-3-carboxylic acid methyl ester222 (1R,2S,5S)-3-[2-((S)-2-Phenyl-chroman-6-yloxy)- H 477.09 1.25 0.9thiazole-5-carbonyl]-3-aza-bicyclo[3.1.0]hexane-2- carboxylic acidmethyl ester 223 (S)-4,4-Dimethyl-1-[2-((S)-2-phenyl-chroman-6- H 493.251.41 1.3 yloxy)-thiazole-5-carbonyl]-pyrrolidine-2-carboxylic acidmethyl ester 224 4-Methyl-1-[2-((S)-2-phenyl-chroman-6-yloxy)- H 479.221.37 0.3 thiazole-5-carbonyl]-pyrrolidine-3-carboxylic acid methyl ester225 3-Methyl-1-[2-((S)-2-phenyl-chroman-6-yloxy)- H 479.25 1.37 0.5thiazole-5-carbonyl]-pyrrolidine-3-carboxylic acid methyl ester 226(2R,3S)-2-Hydroxy-5-methyl-3-{[2-((S)-2-phenyl- H 511.29 1.38 0.7chroman-6-yloxy)-thiazole-5-carbonyl]-amino}- hexanoic acid methyl ester227 (3S,4S)-5-Cyclohexyl-3-hydroxy-4-{[2-((S)-2- H 579.33 1.46 30% (1)phenyl-chroman-6-yloxy)-thiazole-5-carbonyl]- amino}-pentanoic acidethyl ester 228 (R)-4-Methyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H523.32 1.48 46% (1) thiazole-5-carbonyl]-amino}-pentanoic acid tert-butyl ester 229 (S)-4-Methyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H523.33 1.48 44% (1) thiazole-5-carbonyl]-amino}-pentanoic acid tert-butyl ester 230 4-Methyl-2-({[2-((S)-2-phenyl-chroman-6-yloxy)- H 509.281.44 1.5 thiazole-5-carbonyl]-amino}-methyl)-pentanoic acid ethyl ester231 2,4-Dimethyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 495.27 1.44 1.5thiazole-5-carbonyl]-amino}-pentanoic acid methyl ester 2322-[2-(6-Methyl-pyridin-3-yl)-chroman-6-yloxy]- H 449.21 0.88 1.5thiazole-5-carboxylic acid (isoxazol-5-ylmethyl)- amide 2332-Methyl-3-phenyl-2-{[2-((S)-2-phenyl-chroman-6- H 515.24 1.25 0.8yloxy)-thiazole-5-carbonyl]-amino}-propionic acid 234(S)-4,4-Dimethyl-1-[2-((S)-2-phenyl-chroman-6- H 479.21 1.22 1.0yloxy)-thiazole-5-carbonyl]-pyrrolidine-2-carboxylic acid 2354-Methyl-1-[2-((S)-2-phenyl-chroman-6-yloxy)- H 465.21 1.18 0.5thiazole-5-carbonyl]-pyrrolidine-3-carboxylic acid 236(2R,3S)-2-Hydroxy-5-methyl-3-{[2-((S)-2-phenyl- H 497.25 1.21 1.6chroman-6-yloxy)-thiazole-5-carbonyl]-amino}- hexanoic acid 237(R)-4-Methyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 467.24 1.24 0.8thiazole-5-carbonyl]-amino}-pentanoic acid 2384-Methyl-2-({[2-((S)-2-phenyl-chroman-6-yloxy)- H 481.26 1.24 0.3thiazole-5-carbonyl]-amino}-methyl)-pentanoic acid 2393-Methyl-1-[2-((S)-2-phenyl-chroman-6-yloxy)- H 465.21 1.18 2.4thiazole-5-carbonyl]-pyrrolidine-3-carboxylic acid 240(3S,4S)-5-Cyclohexyl-3-hydroxy-4-{[2-((S)-2- H 551.28 1.27 1.1phenyl-chroman-6-yloxy)-thiazole-5-carbonyl]- amino}-pentanoic acid 241(S)-4-Methyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 467.24 1.24 0.6thiazole-5-carbonyl]-amino}-pentanoic acid 2422,4-Dimethyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 481.25 1.26 0.7thiazole-5-carbonyl]-amino}-pentanoic acid 2431-[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 519.19 1.22 0.7carbonyl]-4-trifluoromethyl-pyrrolidine-3-carboxylic acid 244(S)-3-Phenyl-2-{[2-((S)-2-phenyl-chroman-6-yloxy)- H 501.23 1.23 0.6thiazole-5-carbonyl]-amino}-propionic acid 245{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazol-5- H 411.28 1.01 0.1ylmethyl]-amino}-acetic acid methyl ester 246{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazol-5- H 397.19 1.13 0.6ylmethyl]-amino}-acetic acid 2472-[2-(5-Fluoro-pyridin-3-yl)-chroman-6-yloxy]- H 497.16 1.26 0.7thiazole-5-carboxylic acid (2-chloro-pyridin-4- ylmethyl)-amide 2482-[2-(5-Fluoro-pyridin-3-yl)-chroman-6-yloxy]- H 453.17 1.21 0.8thiazole-5-carboxylic acid (isoxazol-5-ylmethyl)- amide 2492-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5- H 398.2 0.95 1.4carboxylic acid (2-hydroxy-ethyl)-amide 250{[2-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5- H 426.19 1.03 1.2carbonyl]-amino}-acetic acid methyl ester 2512-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5- H 474.25 1.1 1.1carboxylic acid ((S)-2-hydroxy-1-phenyl-ethyl)- amide 2522-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5- J 452.22 2.95 3.2carboxylic acid (1-cyclopropyl-3-hydroxy-propyl)- amide 2532-[2-(5-Fluoro-pyridin-3-yl)-chroman-6-yloxy]- H 416.18 1.14 0.6thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide 2542-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 450.39 1.14 0.4carboxylic acid ((3S,4S)-4-methoxy-pyrrolidin-3-yl)- amide 2552-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 434.21 1.14 0.3carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-yl)-amide 2562-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 408.2 1.12 0.3 carboxylicacid ((1S,2S)-2-amino-cyclopropyl)- amide 2572-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 422.22 1.13 0.4carboxylic acid (3-amino-cyclobutyl)-amide 2582-{(2-Hydroxy-ethyl)-[2-((S)-2-phenyl-chroman-6- H 427.25 1.08 0.2yloxy)-thiazol-5-ylmethyl]-amino}-ethanol 259((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-[2-(2-pyridin- J 438.25 2.79 1.83-yl-chroman-6-yloxy)-thiazol-5-yl]-methanone 260{[2-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5- H 412.17 0.95 38% (1)carbonyl]-amino}-acetic acid 261(2S,3S)-3-Methyl-2-{[2-(2-pyridin-3-yl-chroman-6- H 482.26 1.22 3.1yloxy)-thiazole-5-carbonyl]-amino}-pentanoic acid methyl ester 262(S)-3-Phenyl-2-{[2-(2-pyridin-3-yl-chroman-6-yloxy)- H 530.27 1.24 0.8thiazole-5-carbonyl]-amino}-propionic acid ethyl ester 263(S)-3-Methyl-2-{[2-(2-pyridin-3-yl-chroman-6-yloxy)- H 482.26 1.22 25.2thiazole-5-carbonyl]-amino}-butyric acid ethyl ester 264(S)-3,3-Dimethyl-2-{[2-(2-pyridin-3-yl-chroman-6- J 482.25 3.84 3.1yloxy)-thiazole-5-carbonyl]-amino}-butyric acid methyl ester 2652-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5- H 423.2 0.87 7.3carboxylic acid (3-amino-cyclobutyl)-amide hydrochloride 2662-{[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazol-5- H 383.2 1.08 0.1ylmethyl]-amino}-ethanol 2672-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5- H 409.17 0.86 0.6carboxylic acid ((1S,2S)-2-amino-cyclopropyl)- amide hydrochloride 2682-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5- H 435.18 0.88 2.5carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-yl)-amide 2692-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5- H 453.19 0.9 2.6carboxylic acid ((3S,4S)-4-methoxy-pyrrolidin-3-yl)- amide hydrochloride270 (23,3S)-3-Methyl-2-{[2-(2-pyridin-3-yl-chroman-6- H 468.23 1.12 12.5yloxy)-thiazole-5-carbonyl]-amino}-pentanoic acid 271(S)-3-Phenyl-2-{[2-(2-pyridin-3-yl-chroman-6-yloxy)- H 502.22 1.13 12.1thiazole-5-carbonyl]-amino}-propionic acid 272(S)-3-Methyl-2-{[2-(2-pyridin-3-yl-chroman-6-yloxy)- H 454.21 1.08 15.6thiazole-5-carbonyl]-amino}-butyric acid 273(S)-3,3-Dimethyl-2-{[2-(2-pyridin-3-yl-chroman-6- H 467.89 1.13 10.1yloxy)-thiazole-5-carbonyl]-amino}-butyric acid 2742-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- O 458 96 0.4 carboxylicacid (2-methyl-pyridin-4-ylmethyl)-amide hydrochloride 275(R)-2-{[2-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole- H 440.22 1.08 3.15-carbonyl]-amino}-propionic acid methyl ester 276(S)-2-{[2-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole- H 454.24 1.13 0.45-carbonyl]-amino}-propionic acid ethyl ester 2772-[2-(6-Chloro-pyridin-3-yl)-chroman-6-yloxy]- H 469.13 1.26 2.0thiazole-5-carboxylic acid (isoxazol-5-ylmethyl)- amide hydrochloride278 2-[2-(6-Chloro-pyridin-3-yl)-chroman-6-yloxy]- H 513.12 1.3 1.3thiazole-5-carboxylic acid (2-chloro-pyridin-4- ylmethyl)-amidehydrochloride 279 2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 468.391.13 0.5 carboxylic acid (2-dimethylamino-ethyl)-amide 2802-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 471.19 1.47 38% (1)carboxylic acid (4-isopropyl-phenyl)-amide 2812-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 395.16 1.36 0.6carboxylic acid propylamide 282(3,3-Dimethyl-piperazin-1-yl)-[2-((S)-2-phenyl- H 450.2 1.13 1.2chroman-6-yloxy)-thiazol-5-yl]-methanone 283(3aS,6aS)-Hexahydro-pyrrolo[3,4-b]pyrrol-1-yl-[2- H 448.22 1.01 0.6((S)-2-phenyl-chroman-6-yloxy)-thiazol-5-yl]- methanone hydrochloride284 2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 408.2 1 0.2carboxylic acid ((S)-2-amino-cyclopropyl)-amide hydrochloride 285((3R,4R)-4-Methyl-3-methylamino-piperidin-1-yl)-[2- H 464.26 1.02 0.9((S)-2-phenyl-chroman-6-yloxy)-thiazol-5-yl]- methanone hydrochloride286 (2-Dimethylaminomethyl-morpholin-4-yl)-[2-((S)-2- J 480.2 3.53 1.5phenyl-chroman-6-yloxy)-thiazol-5-yl]-methanone 2872-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 450.22 1.14 0.5carboxylic acid (piperidin-2-ylmethyl)-amide 288[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazol-5-yl]- H 421.23 1.27 0.4piperidin-1-yl-methanone 2892-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 454.14 0.98 0.3carboxylic acid (3-amino-propyl)-amide 290(2,7-Diaza-spiro[4.5]dec-2-yl)-[2-((S)-2-phenyl- H 475.85 1 0.6chroman-6-yloxy)-thiazol-5-yl]-methanone 291(2-Aminomethyl-pyrrolidin-1-yl)-[2-((S)-2-phenyl- H 436.21 1.14 0.4chroman-6-yloxy)-thiazol-5-yl]-methanone 292(3-Amino-pyrrolidin-1-yl)-[2-((S)-2-phenyl-chroman- H 422.18 1.11 0.36-yloxy)-thiazol-5-yl]-methanone 2932-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-5- H 476.25 1.17 1.0carboxylic acid ((1R,2R,3S,4S)-3-aminomethyl-bicyclo[2.2.1]hept-2-yl)-amide 294{[2-(2-Phenyl-chroman-6-yloxy)-thiazole-5- H 425.1 1.31 0.2carbonyl]-amino}-acetic acid methyl ester 2952-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic H 397.08 1.25 0.4acid (2-hydroxy-ethyl)-amide 2963-(3,5-Dimethyl-isoxazol-4-yl)-N-[2-((S)-2-phenyl- H 490.18 1.32 0.4chroman-6-yloxy)-thiazol-5-ylmethyl]-propionamide 297N-[2-((S)-2-Phenyl-chroman-6-yloxy)-thiazol-5- H 503.21 1.26 1.1ylmethyl]-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)- propionamide 298((R)-3-Hydroxy-pyrrolidin-1-yl)-[2-(2-phenyl- H 423.12 1.26 0.6chroman-6-yloxy)-thiazol-5-yl]-methanone 2992-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic H 411.27 1.28 0.4acid (2-hydroxy-ethyl)-amide 300((R)-3-Hydroxy-pyrrolidin-1-yl)-[2-(2-o-tolyl- H 437.17 1.3 0.2chroman-6-yloxy)-thiazol-5-yl]-methanone 3012-[2-(4-Methanesulfonyl-phenyl)-chroman-6-yloxy]- H 512.15 1.19 6.9thiazole-5-carboxylic acid (isoxazol-5-ylmethyl)- amide 3022-Amino-N-[2-((S)-2-phenyl-chroman-6-yloxy)- H 396.13 1.12 0.4thiazol-5-ylmethyl]-acetamide 303(S)-2-Amino-N-[2-((S)-2-phenyl-chroman-6-yloxy)- H 410.15 1.14 0.3thiazol-5-ylmethyl]-propionamide 304(S)-2-Amino-3-phenyl-N-[2-((S)-2-phenyl-chroman- H 486.2 1.18 1.96-yloxy)-thiazol-5-ylmethyl]-propionamide 3052-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic H 427.13 1.23 0.3acid (2,3-dihydroxy-propyl)-amide 306{[2-(2-Phenyl-chroman-6-yloxy)-thiazole-5- H 467.15 1.39 0.5carbonyl]-amino}-acetic acid tert-butyl ester 307{[2-(2-Phenyl-chroman-6-yloxy)-thiazole-5- H 453.16 1.37 0.2carbonyl]-amino}-acetic acid isopropyl ester 308{[2-(2-Phenyl-chroman-6-yloxy)-thiazole-5- H 439.13 1.34 0.2carbonyl]-amino}-acetic acid ethyl ester 3092-(2-Pyrazin-2-yl-chroman-6-yloxy)-thiazole-5- O 436 1.32 4.7 carboxylicacid (isoxazol-5-ylmethyl)-amide 3102-(2-Pyrazin-2-yl-chroman-6-yloxy)-thiazole-5- O 480 1.49 2.6 carboxylicacid (2-chloro-pyridin-4-ylmethyl)-amide 3112-{[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- J 383.2 3.33 0.1ylmethyl]-amino}-ethanol 3122-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic H 441.21 1.1 0.1 acidbis-(2-hydroxy-ethyl)-amide 313(4-Methyl-piperazin-1-yl)-[2-(2-phenyl-chroman-6- H 436.2 1.13 0.4yloxy)-thiazol-5-yl]-methanone 314Morpholin-4-yl-[2-(2-phenyl-chroman-6-yloxy)- H 423.16 1.33 0.1thiazol-5-yl]-methanone 3152-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic K 393.3 1.2 0.0 acidcyclopropylamide 316 [2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-yl]- H421.18 1.4 0.5 piperidin-1-yl-methanone 3172-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic H 409.18 1.4 0.1 acidbutylamide 318 2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic K409.34 1.25 0.1 acid isobutyl-amide 3192-{(2-Hydroxy-ethyl)-[2-(2-phenyl-chroman-6-yloxy)- H 427.2 1.12 0.8thiazol-5-ylmethyl]-amino}-ethanol 3202-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic H 395.15 1.37 0.3acid isopropylamide 3212-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic H 395.22 1.36 0.4acid propylamide 322 2-[2-(2-Ethyl-phenyl)-chroman-6-yloxy]-thiazole-5-H 493.23 1.31 1.1 carboxylic acid [2-(2-oxo-imidazolidin-1-yl)-ethyl]-amide 323 2-[2-(2-Ethyl-phenyl)-chroman-6-yloxy]-thiazole-5- H 504.241.4 0.9 carboxylic acid [2-(3,5-dimethyl-isoxazol-4-yl)- ethyl]-amide324 2-[2-(2-Ethyl-phenyl)-chroman-6-yloxy]-thiazole-5- H 462.2 1.38 0.5carboxylic acid (isoxazol-5-ylmethyl)-amide 3252-((R)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5- N 411.16 1.15 0.2carboxylic acid (2-hydroxy-ethyl)-amide 3262-((S)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5- N 411.16 1.15 0.1carboxylic acid (2-hydroxy-ethyl)-amide 3272-(2-Oxo-pyrrolidin-1-yl)-N-[2-(2-o-tolyl-chroman-6- K 478.21 1.16 0.5yloxy)-thiazol-5-ylmethyl]-acetamide 3282-(2,5-Dioxo-imidazolidin-1-yl)-N-[2-(2-o-tolyl- K 493.26 1.13 0.9chroman-6-yloxy)-thiazol-5-ylmethyl]-acetamide 329Isoxazole-5-carboxylic acid [2-(2-o-tolyl-chroman-6- K 448.2 1.21 0.6yloxy)-thiazol-5-ylmethyl]-amide 3302-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic K 409.27 1.25 0.3acid propylamide 331 2-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]- K462.2 1.24 5.5 thiazole-5-carboxylic acid (isoxazol-5-ylmethyl)- amide332 4-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5- K 423.27 1.2710.0 carboxylic acid propylamide 3334-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5- H 493.2 1.28 0.6carboxylic acid [2-(2-oxo-imidazolidin-1-yl)-ethyl]- amide 3344-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5- H 462.18 1.36 0.5carboxylic acid (isoxazol-5-ylmethyl)-amide 3354-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5- H 425.17 1.3 0.3carboxylic acid (2-hydroxy-ethyl)-amide 336((R)-3-Hydroxy-pyrrolidin-1-yl)-[4-methyl-2-(2-o- H 451.21 1.27 0.6tolyl-chroman-6-yloxy)-thiazol-5-yl]-methanone 3372-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]- H 425.15 1.29 7.6thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide 3382-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]- K 409.21 1.26 8.7thiazole-5-carboxylic acid dimethylamide 3392-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic H 353.15 1.25 0.4acid amide 340 (S)-2-Amino-3-hydroxy-N-[2-(2-phenyl-chroman-6- H 426.161.09 0.9 yloxy)-thiazol-5-ylmethyl]-propionamide hydrochloride 341(S)-Pyrrolidine-2-carboxylic acid [2-(2-phenyl- H 436.19 1.11 0.9chroman-6-yloxy)-thiazol-5-ylmethyl]-amide hydrochloride 3422-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]- H 429.16 1.27 0.4thiazole-5-carboxylic acid (2-hydroxy-ethyl)-amide 3432-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]- H 427.2 1.38 0.5thiazole-5-carboxylic acid propylamide 3442-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]- H 466.17 1.34 0.8thiazole-5-carboxylic acid (isoxazol-5-ylmethyl)- amide 345 Phosphoricacid mono-(2-{[2-((S)-2-o-tolyl- J 491.19 4.36 0.07chroman-6-yloxy)-thiazole-5-carbonyl]-amino}ethyl) ester disodium salt346 N-[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5- K 450.24 1 0.17ylmethyl]-2-pyrrolidin-1-yl-acetamide hydrochloride 3472-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]- H 488.29 1.07 1.5thiazole-5-carboxylic acid [2-(2-oxo-imidazolidin-1- yl)-ethyl]-amide348 2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]- H 413.15 1.35 0.64thiazole-5-carboxylic acid dimethylamide 3492-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]- H 497.18 1.27 0.20thiazole-5-carboxylic acid [2-(2-oxo-imidazolidin-1- yl)-ethyl]-amide350 2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-4- H 397.06 1.26 0.12carboxylic acid (2-hydroxy-ethyl)-amide 3512-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-4- H 395.07 1.38 0.11carboxylic acid propylamide 3522-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-4- K 465.08 1.26 0.21carboxylic acid [2-(2-oxo-imidazolidin-1-yl)-ethyl]- amide 3532-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-4- J 434.17 4.77 0.092carboxylic acid (isoxazol-5-ylmethyl)-amide 3542-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic K 411.22 1.14 0.16acid (2-hydroxy-propyl)-amide 3552-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic K 437.29 1.17 0.25acid (2-hydroxy-cyclopentyl)-amide 356{2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]- K 455.08 1.29 0.54thiazol-5-yl}-((R)-3-hydroxy-pyrrolidin-1-yl)- methanone 3572-(7-Methyl-2-o-tolyl-chroman-6-yloxy)-thiazole-5- K 425.05 1.33 0.60carboxylic acid (2-hydroxy-ethyl)-amide 3582-(7-Methyl-2-o-tolyl-chroman-6-yloxy)-thiazole-5- K 462.15 1.24 0.83carboxylic acid (isoxazol-5-ylmethyl)-amide 3592-(7-Methyl-2-o-tolyl-chroman-6-yloxy)-thiazole-5- K 487.24 1.25 1.5carboxylic acid (2-ethyl-2H-pyrazol-3-ylmethyl)- amide 3602-[2-(2-Fluoro-3-methoxy-phenyl)-chroman-6- K 445.05 1.25 1.8yloxy]-thiazole-5-carboxylic acid (2-hydroxy-ethyl)- amide 3612-[2-(2-Fluoro-3-methoxy-phenyl)-chroman-6- K 482.06 1.31 9.6yloxy]-thiazole-5-carboxylic acid (isoxazol-5- ylmethyl)-amide 3622-[2-(2-Fluoro-3-methoxy-phenyl)-chroman-6- K 509.09 1.32 1.5yloxy]-thiazole-5-carboxylic acid (2-ethyl-2H- pyrazol-3-ylmethyl)-amide363 2-(3-Methyl-2-phenyl-chroman-6-yloxy)-thiazole-5- K 448.06 1.36 1.9carboxylic acid (isoxazol-5-ylmethyl)-amide 3642-(3-Methyl-2-phenyl-chroman-6-yloxy)-thiazole-5- K 411.06 1.3 0.96carboxylic acid (2-hydroxy-ethyl)-amide 3652-[2-(3-Fluoro-2-methoxy-phenyl)-chroman-6- K 509.07 1.35 0.55yloxy]-thiazole-5-carboxylic acid (2-ethyl-2H- pyrazol-3-ylmethyl)-amide366 2-[2-(3-Fluoro-2-methoxy-phenyl)-chroman-6- J 482.11 4.84 0.18yloxy]-thiazole-5-carboxylic acid (isoxazol-5- ylmethyl)-amide 3672-[2-(3-Fluoro-2-methoxy-phenyl)-chroman-6- K 445.04 1.28 0.27yloxy]-thiazole-5-carboxylic acid (2-hydroxy-ethyl)- amide (1)Inhibition in % at 30 μM; IC₅₀ value not determined

Exemplary NMR data of example compounds.

Example 2

¹H-NMR (400 MHz): δ (ppm)=9.29 (t, 1H), 7.95 (s, 1H), 7.30-7.50 (m, 5H),7.20 (m, 1H), 7.15 (dd, 1H), 6.95 (d, 1H), 5.18 (dd, 1H), 4.60 (d, 2H),4.05 (t, 2H), 2.90-3.07 (m, 3H), 2.71-2.81 (m, 1H), 2.62-2.70 (m, 2H),2.15-2.25 (m, 1H), 1.95-2.07 (m, 1H).

Example 14

¹H-NMR: δ (ppm)=8.72 (t, 1H), 7.89 (s, 1H), 7.30-7.48 (m, 5H), 7.27 (s,1H), 7.20 (m, 1H), 7.14 (dd, 1H), 6.93 (d, 1H), 5.17 (dd, 1H), 4.19 (d,2H), 3.69 (s, 3H), 2.95-3.07 (m, 1H), 2.72-2.80 (m, 1H), 2.20 (s, 3H),2.15-2.22 (m, 1H), 1.95-2.07 (m, 1H).

Example 39

¹H-NMR: δ (ppm)=9.20 (t, 1H), 8.86 (d, 1H), 7.98 (s, 1H), 7.39-7.50 (m,5H), 7.30-7.38 (m, 2H), 7.20 (m, 1H), 7.15 (dd, 1H), 6.93 (d, 1H), 5.15(dd, 1H), 4.48 (d, 2H), 2.95-3.07 (m, 1H), 2.72-2.82 (m, 1H), 2.15-2.22(m, 1H), 1.95-2.07 (m, 1H).

Example 125

¹H-NMR: δ (ppm)=7.90 (t, 1H), 7.30-7.50 (m, 5H), 7.10 (s, 1H), 7.07-7.00(m, 2H), 6.93 (d, 1H), 5.15 (dd, 1H), 4.05 (m, 2H), 3.65 (s, 3H),2.95-3.07 (m, 1H), 2.73-2.82 (m, 1H), 2.33/s. 3H), 220/n. 3H), 2.15-2.25(m, 1H), 1.95-2.08 (m, 1H).

Example 134

¹H-NMR: δ (ppm)=9.60-9.25 (br s, 2H), 8.70-8.60 (m, 2H), 7.52-7.30 (m,8H), 7.15 (s, 1H), 7.15-7.08 (m, 1H), 6.93 (d, 1H), 5.15 (dd, 1H), 4.38(s, 2H), 4.22 (s, 2H), 3.05-2.95 (m, 1H), 2.80-2.70 (m, 1H), 2.23-2.15(m, 1H), 2.05-1.95 (m, 1H).

Example 321

¹H-NMR: δ (ppm)=8.49 (t, 1H), 7.87 (s, 1H), 7.30-7.50 (m, 5H), 7.18 (m,1H), 7.13 (dd, 1H), 6.93 (d, 1H), 5.18 (dd, 1H), 3.10-3.20 (m, 2H),2.95-3.07 (m, 1H), 2.72-2.80 (m, 1H), 2.15-2.22 (m, 1H), 1.97-2.07 (m,1H), 1.45-1.55 (m, 2H), 0.87 (t, 3H).

Example 326

¹H-NMR: δ (ppm)=8.52 (t, 1H), 7.90 (s, 1H), 7.43 (m, 1H), 7.19-7.28 (m,4H), 7.13 (m, 1H), 6.91 (d, 1H), 5.29 (d, 1H), 4.75 (t, 1H), 3.45-3.50(m, 2H), 3.22-3.30 (m, 2H), 3.03-3.10 (m, 1H), 2.80-2.86 (m, 1H), 2.30(s, 3H), 2.12-2.20 (m, 1H), 1.89-1.99 (m, 1H).

Example 329

¹H-NMR: δ (ppm)=9.6 (s, 1H), 8.74 (s, 1H), 7.35-7.48 (m, 1H), 7.00-7.30(m, 7H), 6.82-6.95 (m, 1H), 5.20-5.33 (m, 1H), 4.40-4.55 (m, 2H),2.95-3.10 (m, 1H), 2.70-2.86 (m, 1H), 2.35 (s, 3H), 2.10-2.20 (m, 1H),1.85-2.00 (m, 1H).

Example 345

¹H-NMR (400 MHz, D₂O): δ (ppm)=7.73 (s, 1H), 7.41-7.49 (m, 1H),7.20-7.30 (m, 3H), 7.10-7.13 (m, 1H), 7.02-7.08 (m, 1H), 6.87 (d, 1H),5.33 (dd, 1H), 3.77-3.85 (m, 2H), 3.40-3.48 (m, 2H), 2.95-3.07 (m, 1H),2.75-2.85 (m, 1H), 2.30 (s, 3H), 2.10-2.20 (m, 1H), 1.97-2.10 (m, 1H).

Pharmacological Examples

A) Assay Method for Determining the NCX1 Inhibitory Activity

The sodium/calcium exchanger NCX1 can transport calcium ions and sodiumions through the cell membrane. The transport is an exchange of Ca²⁺andNa⁺in two directions depending on membrane potential and ion gradients.At the first direction, named “forward mode” or “calcium export mode”,Ca²⁺is transported out of the cell and Na⁺ is transported into the cell.At the other direction, named “reverse mode” or “calcium import mode”,the transport directions are vice versa. The effect of the compounds ofthe invention on NCX1 was determined in CHO cells stably expressinghuman NCX1 (gene symbol SLC8A1; cf. WO 2009/115238). The assay is basedon the monitoring of intracellular Ca²⁺concentrations using acalcium-sensitive fluorescence dye which is detected by means of a FLIPRdevice (Fluorimetric Imaging Plate Reader, Molecular Devices).

Assay Technology—Reverse Mode

The assay is based on the monitoring of intracellular Ca²⁺concentrationsusing the calcium-sensitive dye Fluo-4. CHO cells expressing NCX1 wereloaded with the dye by means of the acetoxymethyl ester Fluo-4 AM(Invitrogen, F14202), which is cleaved intracellularly by esteraseactivity to yield the charged species of free Fluo-4. After anpreincubation period with the test compound, Gramicidine (Sigma, G5002)was added. Gramicidine is an ionophor for Na⁺ions mediating an increaseof intracellular Na⁺ions. Consequently, intracellular Na⁺ions areexchanged against extracellular Ca²⁺ions (Ca²⁺influx, reverse mode). Theintracellular elevation of Ca²⁺ ions was detected by measuring thefluorescence of Fluo-4 at a wavelength of 520 nm by a FLIPR device.

Briefly, for the reverse mode transport assay 18000 cells per well wereseeded into a 96 well microplate (Corning COSTAR 3904) and incubatedovernight in culture medium (1× Nut Mix F12 (Ham) (Gibco, 21765-029);10% (v/v) fetal calf serum (PAA Gold, A15-649); 450 μg/ml Geneticin(Gibco, 10131-027)). A total volume of 100 μl medium per well was used.For the preparation of the FLIPR assay, the culture medium was removedfrom the plates and 100 μl of dye solution (2 μM Fluo-4 AM; 0.02% (v/v)Pluronic F-127 (20%, Invitrogen, P3000MP); 0.1% (v/v) bovine albuminsolution (30% (v/v), Sigma, A9205) in assay buffer (133.8 mM NaCl(Sigma, S5886); 4.7 mM KCl (Sigma, P3911); 1.25 mM MgCl₂ (Merck,1.05833.0250); 3.5 mM CaCl₂ (Merck, 1.02083.0250); 5 mM glucose (Sigma,G7021); 10 mM Hepes (Sigma, H4034); 0.01% (v/v) Pluronic F-127 (5%,Sigma, P2443); 2.5 mM Probenecid (Maybridge, SB00915EB); pH 7.4)) wereadded into each well. The plates were incubated in the dark at roomtemperature for 80 min. After the incubation period, the dye solutionwas removed and the wells were washed with 100 μl of assay buffer. Then80 μl of a solution of the test compound in assay buffer in differentconcentrations were added into the wells. The plates were incubated at16° C. for 45 min. Meanwhile a 60 μM solution of Gramicidine in assaybuffer (4° C.) was prepared and stored in the wells of a 96 wellmicroplate (96 well microplate, polypropylene, U-shape (Greiner Bio-One,650201)) at 4° C. until measurement was started. The fluorescencemonitoring was performed at 240 measuring points with measurementintervals of 2 sec. After the fifth measuring point, 40 μl of theGramicidine solution were added to each well of the assay plates to givea final Gramicidine concentration of 20 μM. For the determination of theIC₅₀ values the minimal fluorescence value was subtracted from themaximal fluorescence value for all measuring points. The calculation ofthe IC₅₀ values via the percentage inhibitions of Ca²⁺influx into cells(reverse mode) effected by the test compound was performed in Biost@tSpeed 2.0. Results obtained with compounds of the invention are given inTable 1.

Assay Technology—Forward Mode

The assay is based on the monitoring of intracellular Ca²⁺concentrationsusing the PBX Calcium Assay Kit from BD (Becton, Dickinson and Company)with calcium indicator dye 51-9000177BKa (BD, 640177), CHO cellsexpressing NCX1 were loaded with the dye, and after a preincubationperiod with the test compound, lonomycin (Calbiochem, 407950) was added.Ionomycin is an ionophor for Ca²⁺ions mediating an increase ofintracellular Ca²⁺ions. Consequently, intracellular Ca²⁺ions areexchanged against extracellular Na⁺ions (Ca²⁺efflux, forward mode). Thedecrease of intracellular Ca²⁺ions was detected by measuring thefluorescence of the calcium indicator dye at a wavelength of 520 nm by aFLIPR device.

Briefly, similarly as for the reverse mode, for the forward modetransport assay 18000 cells per well were seeded into a 96 wellmicroplate (Corning COSTAR 3904) and incubated overnight in culturemedium (cf. above). A total volume of 100 μl medium per well was used.For the preparation of the FLIPR assay, the culture medium was removedfrom the plates and 100 μl of assay buffer (133.8 mM NaCl (Sigma,S5886); 4.7 mM KCl (Sigma, P3911); 1.25 mM MgCl₂ (Merck, 1.05833.0250);3.5 mM CaCl₂ (Merck, 1.02083.0250); 5 mM glucose (Sigma. G7021); 10 mMHepes (Sigma, H4034); pH 7.4)) were added to each well in a washingstep. Assay buffer was removed, and 100 μl of a solution of the testcompound in assay buffer in different concentrations were added into thewells. Further, 100 μl of dye solution (0.09% (v/v) calcium indicatordye, 9.1% (v/v) signal enhancer (from PBX Calcium Assay Kit); in assaybuffer) were added into each well. The plates were incubated in the darkat room temperature for 60 min. Meanwhile a 10 μM solution of lonomycinin assay buffer (additionally containing 0.05% fetal calf serum (cf.above); 4° C.) was prepared and stored in the wells of a 96 wellmicroplate (96 well microplate, polypropylene, U-shape (Greiner Bio-One,650201)). The fluorescence monitoring was performed at 60 measuringpoints with measurement intervals of 2 sec. After the fifth measuringpoint, 50 μl of the lonomycin solution were added to each well of theassay plate to give a final lonomycin concentration of 2 μM. For thedetermination of the IC₅₀ values the minimal fluorescence value wassubtracted from the maximal fluorescence value for the fifteenth tofifty-fifth measuring points. The calculation of the IC₅₀ values via thepercentage inhibitions of Ca²⁺efflux out of cells (forward mode)effected by the test compound was performed in Biost@t Speed 2.0.Results obtained with compounds of the invention are given in Table 2.“NCX1fw IC₅₀” in Table 2 means the IC₅₀ value for inhibition of NCX1 inforward mode (in μM (micromol/liter)).

TABLE 2 IC₅₀ values for inhibition of the NCX1 in forward mode byexample compounds Example NCX1fw number IC₅₀ 2 1.9 13 0.9 14 2.2 18 0.620 1.2 32 27% (1) 39 1.2 58 8.3 59 0.2 103 3.1 125 20% (1) 134 2.6 15846% (1) 177 0.8 182  8% (1) 189 17% (1) 206 1.6 214 4.5 216 1.9 243 19%(1) 255 0.6 275 9.9 299 0.6 315 3.3 321 1.5 325 26% (1) 326 0.2 327 3.0329 2.5 330 0.35 334 2.1 335 0.9 342 0.7 343 0.8 348 0.8 352 31% (1) 3453 (1) Inhibition in % at 10 μM; IC₅₀ value not determinedB) In vivo Method for Determining the Effect on Heart Contractility

Adult male Sprague-Dawley rats (Harlan VVinkelmann, Borchen, Germany)weighing 340 to 370 g were anesthetized with pentobarbital (100 mg/kgi.p.) and ventilated with a mixture of oxygen (40%) and room air (60%)at a tidal volume of 1 ml/100 g at 60 breaths/min. Body temperature wasmaintained at 36.5±0.3° C. with a heating lamp and was monitored with arectal thermo sensor. Systemic blood pressure was measured in the leftcarotid artery using a pressure transducer (Combitrans; B. BraunMelsungen AG, Melsungen, Germany) connected to a DC-bridge-amplifier(PLUGSYS/ADC Type 663; Harvard Apparatus GmbH, March-Hugstetten,Germany). The electrocardiogram was measured as lead II viasubcutaneously placed electrodes connected to a Heart-Rate-Module(PLUGSYS/HRM Type 669; Harvard Apparatus GmbH, March-Hugstetten,Germany). A micro-tip catheter (2 French, SPR-320; Millar Instruments,Houston, Tex., USA) was placed via the right carotid artery into theleft ventricle, and the left ventricular pressure (LVP) and the enddiastolic pressure (EDP) were continuously measured. Registration of thehemodynamic data was performed via an analog digital converter by apersonal computer using Notocord software (HEM version 3.5). Leftventricular contractility (dp/dt_(max)) and relaxation (dp/dt_(min))were calculated from the LVP signal. For intravenous administration ofthe test compounds, the left jugular vein was prepared and a PP-50catheter was inserted. Test compounds were administered either byintravenous bolus injection or by intravenous infusion by means of aninfusion pump (Unita; B. Braun Melsungen AG, Melsungen, Germany). Testcompounds were dissolved in a mixture of Glycofurol (75%) and Cremophor(25%), and the solution was further diluted with distilled water (1:4).In a typical experiment, several dosages of the test compound wereadministered subsequently at increasing doses. Statistical significanceof the data obtained with drug vs control experiments, in which solventwas administered, was evaluated with the 2-sided ANOVA test (programEverstat). Increases in left ventricular contractility (percentincrease) by example compounds are given in Table 3 in comparison tocontrol experiments in which solvent was administered.

TABLE 3 Increase in left ventricular contractility by example compoundsDose Example Administration (mg per kg of Contractility number mode bodyweight) increase (%) 299 Bolus injection 0.1 mg/kg 36% 0.3 mg/kg 62% 1.0mg/kg 95% 315 Bolus injection 0.1 mg/kg 28% 0.3 mg/kg 41% 1.0 mg/kg 64%326 Bolus injection 0.1 mg/kg 67% 0.3 mg/kg 105% 1.0 mg/kg 138% 327Bolus injection 0.1 mg/kg 9% 0.3 mg/kg 27% 1.0 mg/kg 55% 329 Bolusinjection 0.1 mg/kg 24% 0.3 mg/kg 53% 1.0 mg/kg 101% 330 Bolus injection0.1 mg/kg 50% 0.3 mg/kg 86% 1.0 mg/kg 161% 334 Bolus injection 0.1 mg/kg19% 0.3 mg/kg 41% 1.0 mg/kg 59% 342 Bolus injection 0.1 mg/kg 38% 0.3mg/kg 73% 1.0 mg/kg 146% 343 Bolus injection 0.1 mg/kg 20% 0.3 mg/kg 25%1.0 mg/kg 39% 345 Infusion 0.03 mg/kg/min 32% 0.1 mg/kg/min 85%

The invention claimed is:
 1. A compound of the formula I, in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a pharmaceutically acceptable salt thereof,

wherein Ar is selected from the series consisting of phenyl and a5-membered or 6-membered monocyclic aromatic heterocycle, which are allunsubstituted or substituted by one or more identical or differentsubstituents R1, wherein the heterocycle comprises 1 or 2 identical ordifferent ring heteroatoms selected from the series consisting ofnitrogen, oxygen and sulfur and is bonded via a ring carbon atom; R1 isselected from the series consisting of halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, phenyl, Het1,HO—, (C₁-C₆)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, phenyl-O—, Het1-O— and(C₁-C₆)-alkyl-S(O)_(n)—, and two groups R1 bonded to adjacent ringcarbon atoms in Ar, together with the carbon atoms carrying them, canform a 5-membered to 7-membered mono-unsaturated ring which comprises 0,1 or 2 identical or different ring heteroatoms selected from the seriesconsisting of nitrogen, oxygen and sulfur, and which is unsubstituted orsubstituted by one or more identical or different substituents selectedfrom the series consisting of fluorine and (C₁-C₄)-alkyl; R2 is selectedfrom the series consisting of R5-N(R6)-C(O)—, R5-N(R6)-CH₂—,R7-C(O)—NH—CH₂— and R7-S(O)₂—NH—CH₂—; R3 is selected from the seriesconsisting of hydrogen, halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—; R4is hydrogen or one or more identical or different substituents selectedfrom the series consisting of halogen, (C₁-C₄)-alkyl and(C₁-C₄)-alkyl-O—; R5 and R6 are independently of one another selectedfrom the series consisting of hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₆-C₁₀)-bicycloalkyl, phenyl, Het1 and Het2,wherein (C₁-C₆)-alkyl is unsubstituted or substituted by one or moreidentical or different substituents R10, and (C₃-C₇)-cycloalkyl,(C₆-C₁₀)-bicycloalkyl and Het2 all are unsubstituted or substituted byone or more identical or different substituents R11, or the groups R5and R6, together with the nitrogen atom carrying them, form a 4-memberedto 10-membered, monocyclic or bicyclic, saturated or partiallyunsaturated heterocycle which, in addition to the nitrogen atom carryingR5 and R6, comprises 0 or 1 further ring heteroatom selected from theseries consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents R12; R7 is selected from the series consisting of(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, phenyl, Het2 and Het3, wherein(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and Het2 all are unsubstituted orsubstituted by one or more identical or different substituents R10, andphenyl and Het3 all are unsubstituted or substituted by one or moreidentical or different substituents R13; R10 is selected from the seriesconsisting of R14, fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—,R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—,(C₁-C₆)-alkyl-S(O)_(n)—, R16-N(R17)-, R18-C(O)—N(R17)-,R16-N(R17)-C(O)—, R19-O—C(O)— and R16-N(R17)-S(O)₂—; R11 and R12 areindependently of one another selected from the series consisting of(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-,R19-O—C(O)—(C₁-C₄)-alkyl-, R14, fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—,R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂-O—, (HO)₂P(O)—O—,(HO)₂P(O)—O—CH₂—O—C(O)—O—, (C₁-C₆)-alkyl-S(O)_(n)—, R16-N(R17)-,R18-C(O)—N(R17)-, R16-N(R17)-C(O)—, R19-O—C(O)— and R16-N(R17)-S(O)₂—;R13 is selected from the series consisting of halogen, (C₁-C₄)-alkyl,HO—, (C₁-C₄)-alkyl-O— and R16-N(R17)-, and two substituents R13 bondedto adjacent ring carbon atoms in R7, together with the carbon atomscarrying them, can form a 5-membered to 7-membered mono-unsaturated ringwhich comprises 0, 1 or 2 identical or different ring heteroatomsselected from the series consisting of nitrogen, oxygen and sulfur, andwhich is unsubstituted or substituted by one or more identical ordifferent substituents selected from the series consisting of fluorineand (C₁-C₄)-alkyl; R14 is a 3-membered to 10-membered, monocyclic orbicyclic ring which is saturated, partially unsaturated or aromatic andcomprises 0, 1, 2, 3 or 4 identical or different ring heteroatomsselected from the series consisting of nitrogen, oxygen and sulfur, andwhich is unsubstituted or substituted by one or more identical ordifferent substituents R20; R15 and R18 are independently of one anotherselected from the series consisting of (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,phenyl-(C₁-C₄)-alkyl- and Het1-(C₁-C₄)-alkyl-; R16 and R17 areindependently of one another selected from the series consisting ofhydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, phenyl-(C₁-C₄)-alkyl- andHet1-(C₁-C₄)-alkyl-, or the groups R16 and R17, together with thenitrogen atom carrying them, form a 4-membered to 7-membered, monocyclicsaturated heterocycle which, in addition to the nitrogen atom carryingR16 and R17, comprises 0 or 1 further ring heteroatom selected from theseries consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of fluorine and(C₁-C₄)-alkyl; R19 is selected from the series consisting of hydrogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,phenyl-(C₁-C₄)-alkyl- and Het1-(C₁-C₄)-alkyl-; R20 is selected from theseries consisting of halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₃-C₇)-cycloalkyl, HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—,R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—,(C₁-C₆)-alkyl-S(O)_(n)—, R16-N(R17)-, R18-C(O)—N(R17)-,R18-O—C(O)—N(R17)-, NC—, R18-C(O)—, R16-N(R17)-C(O)—, R19-O—C(O)— andR16-N(R17)-S(O)₂—; Het1 is a 5-membered or 6-membered monocyclicaromatic heterocycle comprising 1 or 2 identical or different ringheteroatoms selected from the series consisting of nitrogen, oxygen andsulfur, which is unsubstituted or substituted by one or more identicalor different substituents selected from the series consisting ofhalogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—; Het2 is a 4-membered to10-membered monocyclic or bicyclic, saturated or partially unsaturatedheterocycle comprising 1 or 2 identical or different ring heteroatomsselected from the series consisting of nitrogen, oxygen and sulfur; Het3is a 5-membered to 10-membered monocyclic or bicyclic aromaticheterocycle comprising 1 or 2 identical or different ring heteroatomsselected from the series consisting of nitrogen, oxygen and sulfur; n isselected from the series consisting of 0, 1 and 2, wherein all numbers nare independent of one another; wherein all phenyl groups, unlessspecified otherwise, are unsubstituted or substituted by one or moreidentical or different substituents selected from the series consistingof halogen, (C₁-C₄)-alkyl and —O—(C₁-C₄)-alkyl; wherein all cycloalkyland bicycloalkyl groups, independently of any other substituents whichcan be present on a cycloalkyl or bicycloalkyl group, can be substitutedby one or more identical substituents selected from the seriesconsisting of fluorine and (C₁-C₄)-alkyl; wherein all alkyl groups,independently of any other substituents which can be present on an alkylgroup, can be substituted by one or more fluorine substituents.
 2. Acompound of the formula I, in any of its stereoisomeric forms or amixture of stereoisomeric forms in any ratio, or a pharmaceuticallyacceptable salt thereof, according to claim 1, wherein Ar is selectedfrom the series consisting of phenyl, thiophenyl, pyridinyl andpyrazinyl, which are all unsubstituted or substituted by one or moreidentical or different substituents R1; R1 is selected from the seriesconsisting of halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, HO—, (C₁-C₆)-alkyl-O—,(C₃-C₇)-cycloalkyl-O—, (C₃-C₇) -cycloalkyl-(C₁-C₄)-alkyl-O— and(C₁-C₆)-alkyl-S(O)_(n)—; R2 is selected from the series consisting ofR5-N(R6)-C(O)—, R5-N(R6)-CH₂—, R7-C(O)—NH—CH₂— and R7-S(O)₂—NH—CH₂—; R3is selected from the series consisting of hydrogen, halogen and(C₁-C₄)-alkyl; R4 is hydrogen or one or more identical or differentsubstituents selected from the series consisting of halogen and(C₁-C₄)-alkyl; R5 and R6 are independently of one another selected fromthe series consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,(C₆-C₁₀)-bicycloalkyl and Het2, wherein (C₁-C₆)-alkyl is unsubstitutedor substituted by one or more identical or different substituents R10,and (C₃-C₇)-cycloalkyl, (C₆-C₁₀)-bicycloalkyl and Het2 all areunsubstituted or substituted by one or more identical or differentsubstituents R11, or the groups R5 and R6, together with the nitrogenatom carrying them, form a 4-membered to 10-membered, monocyclic orbicyclic, saturated heterocycle which, in addition to the nitrogen atomcarrying R5 and R6, comprises 0 or 1 further ring heteroatom selectedfrom the series consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents R12; R7 is selected from the series consisting of(C₁-C₆)-alkyl, Het2 and Het3, wherein (C₁-C₆)-alkyl and Het2 all areunsubstituted or substituted by one or more identical or differentsubstituents R10, and Het3 is unsubstituted or substituted by one ormore identical or different substituents R13; R10 is selected from theseries consisting of R14, fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—,R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—,(HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)-, R18-C(O)—N(R17)-,R16-N(R17)-C(O)— and R19-O—C(O)—; R11 and R12 are independently of oneanother selected from the series consisting of (C₁-C₄)-alkyl,HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-, R19-O—C(O)—(C₁-C₄)-alkyl-,fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—,HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)-,R18-C(O)—N(R17)-, R16-N(R17)-C(O)— and R19-O—C(O)—; R13 is selected fromthe series consisting of halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— andR16-N(R17)-; R14 is a 3-membered to 10-membered, monocyclic or bicyclicring which is saturated, partially unsaturated or aromatic and comprises0, 1, 2 or 3 identical or different ring heteroatoms selected from theseries consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents R20; R15 and R18 are independently of one another selectedfrom the series consisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-; R16 and R17 are independently of oneanother selected from the series consisting of hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, or the groupsR16 and R17, together with the nitrogen atom carrying them, form a5-membered to 6-membered, monocyclic saturated heterocycle which, inaddition to the nitrogen atom carrying R16 and R17, comprises 0 or 1further ring heteroatom selected from the series consisting of nitrogen,oxygen and sulfur, and which is unsubstituted or substituted by one ormore identical or different substituents selected from the seriesconsisting of fluorine and (C₁-C₄)-alkyl; R19 is selected from theseries consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-; R20 is selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₃-C₇)-cycloalkyl, HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—,R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)- and NC—; Het2 isa 4-membered to 10-membered monocyclic or bicyclic, saturated orpartially unsaturated heterocycle comprising 1 or 2 identical ordifferent ring heteroatoms selected from the series consisting ofnitrogen, oxygen and sulfur; Het3 is a 5-membered to 10-memberedmonocyclic or bicyclic aromatic heterocycle comprising 1 or 2 identicalor different ring heteroatoms selected from the series consisting ofnitrogen, oxygen and sulfur; n is selected from the series consisting of0, 1 and 2, wherein all numbers n are independent of one another;wherein all cycloalkyl and bicycloalkyl groups, independently of anyother substituents which can be present on a cycloalkyl or bicycloalkylgroup, can be substituted by one or more identical substituents selectedfrom the series consisting of fluorine and (C₁-C₄)-alkyl; wherein allalkyl groups, independently of any other substituents which can bepresent on an alkyl group, can be substituted by one or more fluorinesubstituents.
 3. A compound of the formula I, in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a pharmaceutically acceptable salt thereof, according to claim 1,wherein Ar is selected from the series consisting of phenyl, thiophenyl,pyridinyl and pyrazinyl, which are all unsubstituted or substituted byone or more identical or different substituents R1; R1 is selected fromthe series consisting of halogen, (C₁-C₆)-alkyl, HO— and(C₁-C₆)-alkyl-O—; R2 is selected from the series consisting ofR5-N(R6)-C(O)—, R5-N(R6)-CH₂—, R7-C(O)—NH—CH₂— and R7-S(O)₂—NH—CH₂—; R3is selected from the series consisting of hydrogen, halogen and(C₁-C₄)-alkyl; R4 is hydrogen or one or more identical or differentsubstituents selected from the series consisting of halogen and(C₁-C₄)-alkyl; R5 and R6 are independently of one another selected fromthe series consisting of hydrogen, (C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl,wherein (C₁-C₆)-alkyl is unsubstituted or substituted by one or moreidentical or different substituents R10, and (C₃-C₇)-cycloalkyl isunsubstituted or substituted by one or more identical or differentsubstituents R11, or the groups R5 and R6, together with the nitrogenatom carrying them, form a 4-membered to 10-membered, monocyclic orbicyclic, saturated heterocycle which, in addition to the nitrogen atomcarrying R5 and R6, comprises 0 or 1 further ring heteroatom selectedfrom the series consisting of nitrogen and oxygen, and which isunsubstituted or substituted by one or more identical or differentsubstituents R12; R7 is selected from the series consisting of(C₁-C₆)-alkyl and Het3, wherein (C₁-C₆)-alkyl is unsubstituted orsubstituted by one or more identical or different substituents R10, andHet3 is unsubstituted or substituted by one or more identical ordifferent substituents R13; R10 is selected from the series consistingof R14, fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—,R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, (HO)₂P(O)—O—CH₂—O—C(O)—O—,R16-N(R17)-, R18-C(O)—N(R17)-, R16-N(R17)-C(O)— and R19-O—C(O)—; R11 andR12 are independently of one another selected from the series consistingof (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, R16-N(R17)-(C₁-C₄)-alkyl-,fluorine, HO—, oxo, (C₁-C₆)-alkyl-O—, HO—S(O)₂—O—, (HO)₂P(O)—O—,R16-N(R17)- and R18-C(O)—N(R17)-; R13 is selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and R16-N(R17)-;R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring which issaturated, partially unsaturated or aromatic and comprises 0, 1, 2 or 3identical or different ring heteroatoms selected from the seriesconsisting of nitrogen, oxygen and sulfur, and which is unsubstituted orsubstituted by one or more identical or different substituents R20; R15and R18 are independently of one another selected from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-; R16 and R17 are independently of oneanother selected from the series consisting of hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, or the groupsR16 and R17, together with the nitrogen atom carrying them, form a5-membered to 6-membered, monocyclic saturated heterocycle which, inaddition to the nitrogen atom carrying R16 and R17, comprises 0 or 1further ring heteroatom selected from the series consisting of nitrogen,oxygen and sulfur, and which is unsubstituted or substituted by one ormore identical or different substituents selected from the seriesconsisting of fluorine and (C₁-C₄)-alkyl; R19 is selected from theseries consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-; R20 is selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,(C₃-C₇)-cycloalkyl, HO—, oxo, (C₁-C₆)-alkyl-O—, R15-C(O)—O—,R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—, R16-N(R17)- and NC—; Het3 isa 5-membered to 10-membered monocyclic or bicyclic aromatic heterocyclecomprising 1 or 2 identical or different ring heteroatoms selected fromthe series consisting of nitrogen, oxygen and sulfur; wherein allcycloalkyl groups, independently of any other substituents which can bepresent on a cycloalkyl group, can be substituted by one or moreidentical substituents selected from the series consisting of fluorineand (C₁-C₄)-alkyl; wherein all alkyl groups, independently of any othersubstituents which can be present on an alkyl group, can be substitutedby one or more fluorine substituents.
 4. A compound of the formula I, inany of its stereoisomeric forms or a mixture of stereoisomeric forms inany ratio, or a pharmaceutically acceptable salt thereof, according toclaim 1, which is a compound of the formula Ie


5. A compound of the formula I, in any of its stereoisomeric forms or amixture of stereoisomeric forms in any ratio, or a pharmaceuticallyacceptable salt thereof, according to claim 1, wherein R2 is selectedfrom the series consisting of R5-N(R6)-C(O)— and R5-N(R6)-CH₂—.
 6. Acompound of the formula I, in any of its stereoisomeric forms or amixture of stereoisomeric forms in any ratio, or a pharmaceuticallyacceptable salt thereof, according to claim 1, wherein R2 is selectedfrom the series consisting of R7-C(O)—NH—CH₂— and R7-S(O)₂-NH—CH₂—.
 7. Acompound of the formula I, in any of its stereoisomeric forms or amixture of stereoisomeric forms in any ratio, or a pharmaceuticallyacceptable salt thereof, according to claim 1, which is a compound ofthe formula Ie,

wherein Ar is phenyl which is unsubstituted or substituted by one ormore identical or different substituents R1; R1 is selected from theseries consisting of halogen, (C₁-C₆)-alkyl, HO— and (C₁-C₆)-alkyl-O—;R2 is selected from the series consisting of R5-N(R6)-C(O)— andR5-N(R6)-CH₂—; R3 is selected from the series consisting of hydrogen,halogen and (C₁-C₄)-alkyl; R4 is hydrogen or one or more identical ordifferent substituents selected from the series consisting of halogenand (C₁-C₄)-alkyl; one of the groups R5 and R6 is hydrogen and the otherof the groups R5 and R6 is selected from the series consisting of(C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, wherein (C₁-C₆)-alkyl isunsubstituted or substituted by one or more identical or differentsubstituents R10, and (C₃-C₇)-cycloalkyl is unsubstituted or substitutedby one or more identical or different substituents R11; R10 is selectedfrom the series consisting of R14, fluorine, HO—, (C₁-C₆)-alkyl-O—,R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—,(HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)- and R18-C(O)—N(R17)-; R11 isselected from the series consisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,R16-N(R17)-(C₁-C₄)-alkyl-, fluorine, HO—, (C₁-C₆)-alkyl-O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, R16-N(R17)- and R18-C(O)—N(R17)-; R14 is a 3-membered to10-membered, monocyclic or bicyclic ring which is saturated, partiallyunsaturated or aromatic and comprises 0, 1, 2 or 3 identical ordifferent ring heteroatoms selected from the series consisting ofnitrogen, oxygen and sulfur, and which is unsubstituted or substitutedby one or more identical or different substituents R20; R15 and R18 areindependently of one another selected from the series consisting of(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-;R16 and R17 are independently of one another selected from the seriesconsisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, or the groups R16 and R17, togetherwith the nitrogen atom carrying them, form a 5-membered to 6-membered,monocyclic saturated heterocycle which, in addition to the nitrogen atomcarrying R16 and R17, comprises 0 or 1 further ring heteroatom selectedfrom the series consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of fluorine and(C₁-C₄)-alkyl; R20 is selected from the series consisting of halogen,(C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-, (C₃-C₇)-cycloalkyl, HO—, oxo,(C₁-C₆)-alkyl-O—, R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, R16-N(R17)- and NC—; wherein all cycloalkyl groups,independently of any other substituents which can be present on acycloalkyl group, can be substituted by one or more identicalsubstituents selected from the series consisting of fluorine and(C₁-C₄)-alkyl; wherein all alkyl groups, independently of any othersubstituents which can be present on an alkyl group, can be substitutedby one or more fluorine substituents.
 8. A compound of the formula I, inany of its stereoisomeric forms or a mixture of stereoisomeric forms inany ratio, or a pharmaceutically acceptable salt thereof, according toclaim 1, which is a compound of the formula Ie,

wherein Ar is phenyl which is unsubstituted or substituted by one ormore identical or different substituents R1; R1 is selected from theseries consisting of halogen, (C₁-C₆)-alkyl, HO— and (C₁-C₆)-alkyl-O—;R2 is selected from the series consisting of R5-N(R6)-C(O)— andR5-N(R6)-CH₂—; R3 is selected from the series consisting of hydrogen,halogen and (C₁-C₄)-alkyl; R4 is hydrogen or one or more identical ordifferent substituents selected from the series consisting of halogenand (C₁-C₄)-alkyl; one of the groups R5 and R6 is hydrogen and the otherof the groups R5 and R6 is selected from the series consisting of(C₁-C₆)-alkyl and (C₃-C₇)-cycloalkyl, wherein (C₁-C₆)-alkyl isunsubstituted or substituted by one or more identical or differentsubstituents R10, and (C₃-C₇)-cycloalkyl is unsubstituted or substitutedby one or more identical or different substituents R11; R10 is selectedfrom the series consisting of fluorine, HO—, (C₁-C₆)-alkyl-O—,R15-C(O)—O—, R15-NH—C(O)—O—, HO—S(O)₂—O—, (HO)₂P(O)—O—,(HO)₂P(O)—O—CH₂—O—C(O)—O—, R16-N(R17)- and R1 8-C(O)—N(R17)-; R11 isselected from the series consisting of (C₁-C₄)-alkyl, HO—(C₁-C₄)-alkyl-,R16-N(R17)-(C₁-C₄)-alkyl-, fluorine, HO—, (C₁-C₆)-alkyl-O—, HO—S(O)₂—O—,(HO)₂P(O)—O—, R16-N(R17)- and R18-C(O)—N(R17)-; R15 and R18 areindependently of one another selected from the series consisting of(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-;R16 and R17 are independently of one another selected from the seriesconsisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, or the groups R16 and R17, togetherwith the nitrogen atom carrying them, form a 5-membered to 6-membered,monocyclic saturated heterocycle which, in addition to the nitrogen atomcarrying R16 and R17, comprises 0 or 1 further ring heteroatom selectedfrom the series consisting of nitrogen, oxygen and sulfur, and which isunsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of fluorine and(C₁-C₄)-alkyl; wherein all cycloalkyl groups, independently of any othersubstituents which can be present on a cycloalkyl group, can besubstituted by one or more identical substituents selected from theseries consisting of fluorine and (C₁-C₄)-alkyl; wherein all alkylgroups, independently of any other substituents which can be present onan alkyl group, can be substituted by one or more fluorine substituents.9. The compound according to claim 1, which is selected from the seriesconsisting of: 2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid[2-(2-oxo-imidazolidin-1-yl)-ethyl]-amide,2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(2-hydroxy-ethyl)-amide,2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acidcyclopropylamide,2-((S)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(2-hydroxy-ethyl)-amide,2-(2-Oxo-pyrrolidin-1-yl)-N-[2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-acetamide,Isoxazole-5-carboxylic acid[2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide,2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid propylamide,4-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(isoxazol-5-ylmethyl)-amide,2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylicacid (2-hydroxy-ethyl)-amide,2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylicacid propylamide, Phosphoric acidmono-(2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethyl)ester, 2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-ylmethyly)-amide,2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid propylamide,2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(2-chloro-pyridin-4-ylmethyl)-amide,2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-amide,1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid[2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide,2-((R)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(2-hydroxy-ethyl)-amide, and[2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-pyridin-4-ylmethyl-amine,or a pharmaceutically acceptable salt thereof.
 10. A process forpreparing the compound of claim 1,

comprising cyclizing a compound of the formula XV to a compound of theformula XVI, converting the compound of the formula XVI into a compoundof the formula II, reacting the compound of the formula II with acompound of the formula III to give a compound of the formula IV, andconverting the compound of the formula IV into a compound of the formulaI, wherein the groups Ar, R3 and R4 in the compounds of the formulae II,III, IV, XV and XVI are defined as in the compounds of the formula I,the group G2 in the compounds of the formula XV is a hydroxy group or anucleophilically substitutable leaving group, the group G3 in thecompounds of the formulae XV and XVI is bromine or (C₁-₄)-alkyl-O—, andthe group Y in the compounds of the formulae III and IV is R50-O—C(O)—,H—C(O)— or NC—, wherein R50 is (C₁-C₄)-alkyl.
 11. The process accordingto claim 10, wherein a compound of the formula Iq is prepared in whichthe chiral carbon atom carrying the group Ar is present in uniformconfiguration,

said process comprising cyclizing a compound of the formula XVa, inwhich the chiral carbon atom carrying the group Ar is present in uniformconfiguration, to a compound of the formula XVIa, converting thecompound of the formula XVIa into a compound of the formula IIa,reacting the compound of the formula IIa with a compound of the formulaIII to give a compound of the formula IVd, and converting the compoundof the formula IVd into a compound of the formula Iq, wherein the groupsAr, R2, R3 and R4 in the compounds of the formulae Iq, IIa, III, IVd,XVa and XVIa are defined as in the compounds of the formula I, the groupG2 in the compounds of the formula XVa, the group G3 in the compounds ofthe formulae XVa and XVIa and the group Y in the compounds of theformulae III and IVd are defined as in compounds of the formulae XV,XVI, III and IV in claim
 10. 12. A pharmaceutical composition,comprising a compound of the formula I, in any of its stereoisomericforms or a mixture of stereoisomeric forms in any ratio, or apharmaceutically acceptable salt thereof, according to claim 1, and apharmaceutically acceptable carrier.
 13. The compound according to claim1, in any of its stereoisomeric forms or a mixture of stereoisomericforms in any ratio, which is2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(2-hydroxy-ethyl)-amide.
 14. The compound according to claim 1, which is2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(2-hydroxy-ethyl)-amide.
 15. The compound according to claim 1, which isisoxazole-5-carboxylic acid[2-(2-o-tolyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide, in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a pharmaceutically acceptable salt thereof.
 16. The compoundaccording to claim 1, in any of its stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, which is2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid propylamide.17. The compound according to claim 1, in any of its stereoisomericforms or a mixture of stereoisomeric forms in any ratio, which is2[2-(5-fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylicacid (2-hydroxy-ethyl)-amide.
 18. The compound according to claim 1,which is phosphoric acidmono-(2-{[2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carbonyl]-amino}-ethyl)ester, or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 1, which is2-((R)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid(2-hydroxy-ethyl)-amide.
 20. The compound according to claim 1, which isphosphoric acidmono-(2-{[2((S)-2-o-tolyl-chroman-6-yloxyythiazole-5-carbonyl]-amino}ethyl)ester disodium salt.